Monocyclic L-Nucleosides, analogs and uses thereof

ABSTRACT

Novel monocyclic L-Nucleoside compounds have the general formula ##STR1## Embodiments of these compounds are contemplated to be useful in treating a wide variety of diseases including infections, infestations, neoplasms, and autoimmune diseases. Viewed in terms of mechanism, embodiments of the novel compounds show immunomodulatory activity, and are expected to be useful in modulating the cytokine pattern, including modulation of Th1 and Th2 response.

This application claims priority to provisional application Ser. No.60/028,585, filed Oct. 16, 1996 and international application no.PCT/US97/18767.

FIELD OF THE INVENTION

The present invention relates to the field of L-nucleosides.

BACKGROUND OF THE INVENTION

The last few decades have seen significant efforts expended in exploringpossible uses of D-nucleoside analogs as antiviral agents. Some of thiswork has borne fruit, and a number of nucleoside analogs are currentlybeing marketed as antiviral drugs, including the HIV reversetranscriptase inhibitors (AZT, ddI, ddC, d4T, and 3TC).

Nucleoside analogs have also been investigated for use as immune systemmodulators, (Bennet, P. A. et al., J Med. Chem., 36, 635, 1993), butagain with less than completely satisfactory results. For example,guanosine analogs such as 8-bromo-, 8-mercapto-, 7-methyl-8-oxoguanosine(Goodman, M. G. Immunopharmacology, 21, 51-68, 1991) and7-thia-8-oxoguanosine (Nagahara, K. J. Med. Chem., 33, 407-415, 1990;U.S. Pat. No. 5,041,426) have been studied over the years for theirability to activate the immune system. These guanosine derivatives showexcellent antiviral and/or antitumor activity in vivo. But, these C₈-substituted guanosines were unable to activate T-cells (Sharma, B. S.et al., Clin. Exp. Metastasis, 9, 429-439, 1991). The same was found tobe true with 6-arylpyrimidinones (Wierenga, W. Ann. N. Y. Acad Sci.,685, 296-300, 1993). In other research, a series of 3-deazapurinenucleosides were synthesized and evaluated as immuno-modulating agents.U.S. Pat. No. 4,309,419 describes the use of 3-deazaadenosine as beingan inhibitor of the immune system. The β-D-nucleoside,β-2'-deoxy-3-deazaguanosine (U.S. Pat. No. 4,950,647) displayed the mostpotent immunoenhancing potency on activated T-cell response.Antiinflamatory and immunosuppressant activity has also been disclosedfor certain 2'-deoxynucleosides (EPO Application 0 038 569). However,these compounds undergo facile in vivo metabolic cleavage of theirglycosyl bond, which effectively inactivates their biological potency.Adenosine derivatives disclosed in U.S. Pat. No. 4,148,888 are alsocatabolized in vivo by deaminase enzymes. In still other research,Levamisole, a thymomimetic immunostimulant (Hadden et al, Immunol.Today, 14, 275-280, 1993), appears to act on the T-cell lineage in amanner similar to thymic hormones. Tucaresol (Reitz et al, Nature, 377,71-75,1995), another T-cell stimulant, is now undergoing clinicaltrials. More recently, 6-substituted purine linker amino acid (Zacharieet al, J. Med. Che., 40, 2883-2894, 1997) has been described as apromising immunostimulant which may be targeted for those disease stateswhich require an increased CTL or Th1 type response.

One possible target of immunomodulation involves stimulation orsuppression of Th1 and Th2 lymphokines. Type I (Th1) cells produceinterleukin 2 (IL-2), tumor necrosis factor (TNFα) and interferon gamma(IFNγ) and they are responsible primarily for cell-mediated immunitysuch as delayed type hypersensitivity and antiviral immunity. Type 2(Th2) cells produce interleukins, IL4, IL-5, IL-6, IL-9, IL-10 and IL-13and are primarily involved in assisting humoral immune responses such asthose seen in response to allergens, e.g. IgE and IgG4 antibody isotypeswitching (Mosmann, 1989, Annu Rev Immunol, 7:145-173). D-guanosineanalogs have been shown to elicit various effects on lymphokines IL-1,IL-6, IFNα and TNFα (indirectly) in vitro (Goodman, 1988, Int JImmunopharmacol, 10, 579-88) and in vivo (Smee et al., 1991, AntiviralRes 15: 229). However, the ability of the D-guanosine analogs such as 7-thio-8-oxoguanosine to modulate Type I or Type 2 cytokines directly in Tcells was ineffective or has not been described.

Significantly, most of the small molecule research has focused on thesynthesis and evaluation of D-nucleosides. This includes Ribavirin(Witkowski, J. T. et al., J. Med. Chem., 15, 1150, 1972), AZT (DeClercq, E. Adv. Drug Res., 17, 1, 1988), DDI (Yarchoan, R. et al.,Science (Washington, D. C.), 245, 412, 1989), DDC (Mitsuya, H. et al.,Proc. Natl. Acad. Sci.

U S. A., 83, 1911, 1986), d4T (Mansuri, M. M. et al., J. Med. Chem., 32,461, 1989) and 3TC (Doong, S. L. et al., Proc. Natl. Acad. Sci. U.S.A.,88, 8495-8599, 1991). In this handful of therapeutic agents, only 3TCwhich contains an unnatural modified L-ribose moiety, the enantiomer ofnatural D-ribose.

After the approval of 3TC by the FDA, a number of nucleosides with theunnatural L-configuration were reported as having potentchemotherapeutic agents against immunodeficiency virus (HIV), hepatitisB virus (HBV), and certain forms of cancer. These include(-)-β-L-1-[2-(hydroxymethyl)-1,3-oxathiolan-4-yl]-5-fluorocytosine (FTC;Furman, P. A., et al, Antimicrob. Agents Chemother., 36, 2686-2692,1992), (-)-β-L-2',3'-dideoxypentofuranosyl-5-flurocytosine (L-FddC;Gosselin, G., et al, Antimicrob. Agents Chemother., 38, 1292-1297,1994), (-)-β-L-1-[2-(hydroxymethyl)-1,3-oxathiolan-4-yl]cytosine[(-)-OddC; Grove, K. L., et al, Cancer Res., 55, 3008-3011, 1995],2',3'-dideoxy-β-L-cystidine (β-L-ddC; Lin, T. S., et al, J. Med. Chem.,37, 798-803, 1994), 2'fluoro-5-methyl-β-L-arabinofuranosyluracil(L-FMAU; U.S. Pat. No. 5,567,688),2',3'-dideoxy-2',3'-didehydro-β-L-cystidine (β-L-d4C; Lin, T. S., et al,J. Med. Chem., 39, 1757-1759, 1996),2',3'-dideoxy-2',3'-didehydro-β-L-5-fluorocystidine (β-L-Fd4C; Lin, T.S., et al, J. Med.

Chem., 39, 1757-1759, 1996), L-cyclopentyl carbocyclic nucleosides(Wang, P., et al, Tetrahedron Letts., 38, 4207-4210, 1997) and varietyof 9-(2'-deoxy-2'-fluoro-β-L-arabinofuranosyl)purine nucleosides (Ma,T.' et al, J. Med. Chem., 40, 2750-2754, 1997). Other research onL-nucleosides has also been reported. U.S. Pat. No. 5,009,698, forexample, describes the synthesis and use of L-adenosine to stimulate thegrowth of a plant. WO 92/08727 describes certain L-2'-deoxyuridines andtheir use for treating viruses. Spadari, S., et al, J. Med. Chem., 35,4214-4220, 1992, describes the synthesis of certain L-β-nucleosidesuseful for treating viral infections including Herpes Simplex Virus TypeI. U.S. Pat. No. 5,559,101 describes the synthesis of α- andβ-L-ribofuranosyl nucleosides, processes for their preparation,pharmaceutical composition containing them, and method of using them totreat various diseases in mammals. A German patent (De 195 18 216)describes the synthesis of 2'-fluoro-2'-deoxy-L-β-arabinofuranosylpyrimidine nucleosides. U.S. Pat. Nos. 5,565,438 and 5,567,688 describethe synthesis and utility of L-FMAU. WO Patent 95/20595 describes thesynthesis of 2'-deoxy-2'-fluoro-L-β-arbinofuranosyl purine andpyrimidine nucleosides and method of treating HBV or EBV. U.S. Pat. No.5,567,689 describes methods for increasing uridine levels withL-nucleosides. WO patent 96/28170 describes a method of reducing thetoxicity of D-nucleosides by co-administering an effective amount ofL-nucleoside compounds.

Significantly, while some of the known L-nucleosides have shown potentantiviral activity with lower toxicity profiles than theirD-counterparts, none of these L-nucleoside compounds have been shown toposses immunomodulatory properties. Moreover, at present there is noeffective treatment for the modulation of the immune system wherelymphokine profiles (Th1 and Th2 subsets) have been implicated. Thus,there remains a need for novel L-nucleoside analogs, especially a needfor L-nucleoside analogs which modulate the immune system, and mostespecially L-nucleoside analogs which specifically modulate Th1 and Th2.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to novel L-nucleoside compounds, theirtherapeutic uses and synthesis.

In one aspect of the invention, novel L-nucleoside compounds areprovided according to the following formula: ##STR2## wherein: A isindependently selected from N or C;

B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR¹,CCONH₂, CCH₃, C--R² or P; R₁ is independently H, lower alkyl, loweralkylamines, COCH₃, lower alkyl alkenyl, lower alkyl vinyl or loweralkyl aryls. R² is independently H, OH, halogens, CN, N₃, NH₂, C(═O)NH₂,C(═S)NH₂, C(═NH)NH₂.HCl, C(═NOH)NH₂, C(═NH)OMe, lower alkyl, loweralkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl arylsor substituted heterocycles;

D is independently selected from CH, CO, N, S, Se, O, NR¹, CCONH₂, CCH₃,C--R², P or nothing, where R¹ is independently H, O, lower alkyl, loweralkylamines, COCH₃, lower alkyl alkenyl, lower alkyl vinyl or loweralkyl aryls, and R² is independently H, OH, halogens, CN, N₃, NH₂, loweralkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, loweralkyl aryls or substituted heterocycles;

X is independently O, S, CH₂ or NR; where R is COCH₃ ;

R₁ and R₄ are independently selected from H, CN, N₃, CH₂ OH, lower alkyland lower alkyl amines;

R₂, R₃, R₅, R₆, R₇ and R₈ are independently selected from H, OH, CN, N₃,halogens, CH₂ OH, NH₂, OCH₃, NHCH₃, ONHCH₃, SCH₃, SPh, alkenyl, loweralkyl, lower alkyl amines and substituted heterocycles; and

R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are not all substituted at the sametime; such that

when R₂ ═R₃ ═H, then R₇ and R₈ are hydrogens or nothing;

when R₁, R₄ or R₅ are substituted, then R₇ ═R₈ ═H and R₂ ═R₃ ═OH;

when R₂ or R₃ are substituted, then R₇ and R₈ are H or OH;

when R₇ or R₈ are substituted, then R₂ and R₃ are H or OH;

when R₇ and R₈ are hydroxyl, then R₂ and R₃ are not OH;

when A═N; B═CO; C═N or NH; D═CO or C--NH₂ ; E is CH or C-substituted;F═CH; X═O, S or CH₂, then R₂ will not be H, OH, CH₃, halogens, N₃, CN,SH, SPh, CH₂ OH, CH₂ OCH₃, CH₂ SH, CH₂ F, CH₂ N₃, aryl, aryloxy orheterocycles;

when A═N; B═CO; C═N or NH; D═CO or C--NH₂ ; E is CH, C--CH₃ or halogen;F═CH; X═N--COCH₃, then R₂ will not be H or OH;

when A═N; B═CH; C═CH or CH₃ ; D═CH or C--CH₃ ; E is CH, C--CH₃ orC--CONH₂ ; F═CH; X═O, or CH₂, then R₂ will not be H or OH;

when A═N; B═N, CO or CH; C═CH, C--Cl or C--OCH₃ ; D═CH or C--Ph; E isCH, C--Cl or C--Ph; F═N or CO; X═O, then R₂ will not be H or OH;

when A═N; B═CO or CS; C═N or NH; D═CO or C--NH₂ ; E is CH or N; F═N orCH; X═O, then R₂ will not be H or OH; and

when A═C; B═CH; C═NH; D═CO, CS or C--NH₂ ; E is N or NH; F═CO or CH;X═O, then R₂ will not be H or OH.

In one class of preferred embodiments of the invention, the compoundcomprises a ribofuranosyl moiety, and in a particularly preferredembodiment the compound comprises L-Ribavirin.

In another aspect of the invention, a pharmaceutical compositioncomprises a therapeutically effective amount of a compound of Formulas 1and 3-5, or a pharmaceutically acceptable ester or salt thereof admixedwith at least one pharmaceutically acceptable carrier.

In yet another aspect of the invention, a compound according to Formulas1 and 3-5 is used in the treatment of any condition which respondspositively to administration of the compound, and according to anyformulation and protocol which achieves the positive response. Amongother things it is contemplated that compounds of Formula I may be usedto treat an infection, an infestation, a cancer or tumor or anautoimmune disease.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-12 are schematic representations of synthetic chemical stepswhich may be used to prepare compounds in the examples section below.

FIGS. 13-14 are graphical representations of the effect of D-Ribavirinand L-Ribavirin on IL-2 TNFα, IFN-γ, IL-4 and IL-5 levels of activatedT-cells.

FIG. 15 is a graphical representation of the effects of L-Ribavirin onthe inflammatory ear response to dinitrofluorobenzene.

FIGS. 16-26 are schematic representations of synthetic chemical stepswhich may be used to prepare compounds in the examples section below.

DETAILED DESCRIPTION

Where the following terms are used in this specification, they are usedas defined below.

The term "nucleoside" refers to a compound composed of any pentose ormodified pentose moiety attached to a specific position of a heterocycleor to the natural position of a purine (9-position) or pyrimidine(1-position) or to the equivalent position in an analog.

The term "nucleotide" refers to a phosphate ester substituted on the5'-position of a nucleoside.

The term "heterocycle" refers to a monovalent saturated or unsaturatedcarbocyclic radical having at least one hetero atom, such as N, O or S,within the ring each available position of which can be optionallysubstituted, independently, with, e.g., hydroxy, oxo, amino, imino,lower alkyl, bromo, chloro and/or cyano. Included within this class ofsubstituents are purines, pyrimidines.

The term "purine" refers to nitrogenous bicyclic heterocycles.

The term "pyrimidine" refers to nitrogenous monocyclic heterocycles.

The term "D-nucleosides" that is used in the present invention describesto the nucleoside compounds that have a D-ribose sugar moiety (e.g.,Adenosine).

The term "L-nucleosides" that is used in the present invention describesto the nucleoside compounds that have an L-ribose sugar moiety.

The term "L-configuration" is used throughout the present invention todescribe the chemical configuration of the ribofuranosyl moiety of thecompounds that is linked to the nucleobases. The L-configuration of thesugar moiety of compounds of the present invention contrasts with theD-configuration of ribose sugar moieties of the naturally occurringnucleosides such as cytidine, adenosine, thymidine, guanosine anduridine.

The term "C-nucleosides" is used throughout the specification todescribe the linkage type that formed between the ribose sugar moietyand the heterocyclic base. In C-nucleosides, the linkage originates fromthe C-1 position of the ribose sugar moiety and joins the carbon of theheterocyclic base. The linkage that forms in C-nucleosides are carbon tocarbon type.

The term "N-nucleosides" is used throughout the specification todescribe the linkage type that formed between the ribose sugar moietyand the heterocyclic base. In N-nucleosides, the linkage originates fromthe C-1 position of the ribose sugar moiety and joins the nitrogen ofthe heterocyclic base. The linkage that forms in N-nucleosides arecarbon to nitrogen type.

The term "protecting group" refers to a chemical group that is added to,oxygen or nitrogen atom to prevent its further reaction during thecourse of derivatization of other moieties in the molecule in which theoxygen or nitrogen is located. A wide variety of oxygen and nitrogenprotecting groups are known to those skilled in the art of organicsynthesis.

The term "lower alkyl" refers to methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, i-butyl or n-hexyl. This term is further exemplifiedto a cyclic, branched or straight chain from one to six carbon atoms.

The term "aryl" refers to a monovalent unsaturated aromatic carbocyclicradical having a single ring (e.g., phenyl) or two condensed rings(e.g., naphthyl), which can optionally be substituted with hydroxyl,lower alky, chloro, and/or cyano.

The term "heterocycle" refers to a monovalent saturated or unsaturatedcarbocyclic radical having at least one hetero atom, such as N, O, S, Seor P, within the ring, each available position of which can beoptionally substituted or unsubstituted, independently, with e.g.,hydroxy, oxo, amino, imino, lower alkyl, bromo, chloro, and/or cyano.

The term "monocyclic" refers to a monovalent saturated carbocyclicradical having at least one hetero atom, such as O, N, S, Se or P,within the ring, each available position of which can be optionallysubstituted, independently, with a sugar moiety or any other groups likebromo, chloro and/or cyano, so that the monocyclic ring systemeventually aromatized [e.g., Thymidine;1-(2'-deoxy-β-D-erythro-pentofuranosyl)thymine].

The term "immunomodulators" refers to natural or synthetic productscapable of modifying the normal or aberrant immune system throughstimulation or suppression.

The term "effective amount" refers to the amount of a compound offormula (I) which will restore immune function to normal levels, orincrease immune function above normal levels in order to eliminateinfection.

The compounds of Formula I may have multiple asymmetric centers.Accordingly, they may be prepared in either optically active form or asa racemic mixture. The scope of the invention as described and claimedencompasses the individual optical isomers and non-racemic mixturesthereof as well as the racemic forms of the compounds of Formula I.

The terms "α" and "β" indicate the specific stereochemical configurationof a substituent at an asymmetric carbon atom in a chemical structure asdrawn. The compounds described herein are all in the L-furanosylconfiguration.

The term "enantiomers" refers to a pair of stereoisomers that arenon-superimposable mirror images of each other. A mixture of a pair ofenantiomers, in a 1:1 ratio, is a "racemic" mixture.

The term "isomers" refers to different compounds that have the sameformula. "Stereoisomers" are isomers that differ only in the way theatoms are arranged in space.

A "pharmaceutically acceptable salts" may be any salts derived frominorganic and organic acids or bases.

Compounds of the present invention are named according to the conventionof Formula II: ##STR3##

Compounds

The compounds of the present invention are generally described byFormula I. There are, however, several subsets of compounds which are ofparticular interest, including compounds according to Formulas III, IVand V below.

Compounds according to Formula III have the following structure:##STR4## wherein: X is independently O, S, CH₂ and NR, where R is COCH₃;

R' and R" are independently selected from H, CN, C(═O)NH₂, NH₂,C(═S)NH₂, C(═NH)NH₂.HCl, C(═NOH)NH₂, C(═NH)OMe, heterocycles, halogens,lower alkyl or lower alkyl aryl;

R₁ and R₄ are independently selected from H, CN, N₃, CH₂ OH, lower alkylor lower alkyl amines; and

R₂, R₃, R₅, R₆, R₇ and R₈ are independently selected from H, OH, CN, N₃,halogens, CH₂ OH, NH₂, OCH₃, NHCH₃, ONHCH₃, SCH₃, SPh, alkenyl, loweralkyl, lower alkyl amines or substituted heterocycles; such that

when R₂ ═R₃ ═H, then R₇ and R₈ are hydrogens or nothing.

In compounds of Formula III, R' is preferably carboxamide or CN and R"is hydrogen or halogens; R₁ ═R₄ ═R₅ ═R₇ ═R₈ ═H and R₂ ═R₃ ═OH, andpreferably X is oxygen.

Compounds according to Formula IV have the following structure: ##STR5##wherein: A is independently selected from N or C;

B, C, E and F are independently selected from CH, CO, N, S, Se, O, NR¹,CCONH₂, CCH₃, C--R₂ or P; R¹ is independently H, lower alkyl, loweralkylamines, COCH₃, lower alkyl alkenyl, lower alkyl vinyl or loweralkyl aryls. R² is independently H, OH, halogens, CN, N₃, NH₂, C(═O)NH₂,C(═S)NH₂, C(═NH)NH₂.HCl, C(═NOH)NH₂, C(═NH)OMe, lower alkyl, loweralkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl arylsor substituted heterocycles;

X is independently O, S, CH₂ or NR; where R is COCH₃ ;

R₁ and R₄ are independently selected from H, CN, N₃, CH₂ OH, lower alkylor lower alkyl amines; and

R₂, R₃, R₅, R₆, R₇ and R₈ are independently selected from H, OH, CN, N₃,halogens, NH₂, CH₂ OH, OCH₃, NHCH₃, ONHCH₃, SCH₃, SPh, alkenyl, allyl,lower alkyl, lower alkyl amines or substituted heterocycles; such that

when R₂ ═R₃ ═H, then R₇ and R₈ are hydrogens or nothing;

when A is carbon; B═E═N; C is N--Ph, then F is not CH;

when A═N; C is CH; B═E═C--CH₃, then F is not nitrogen; and

when A is carbon, B═N; C═C--CONH₂ ; E═CH; F═S, then X is not CH₂.

In compounds of Formula IV, R₁ is preferably H, lower alkyl or allyl; R²is preferably H, OH, halogens, CN, N₃, NH₂, C(═O)NH₂, C(═S)NH₂,C(═NH)NH₂.HCl, C(═NOH)NH₂ or C(═NH)OMe; and when R₁ ═R₄ ═R₅ ═R₇ ═R₈ ═H,then preferably R₂ ═R₃ ═OH and preferably X is oxygen.

Compounds according to Formula V have the following structure: ##STR6##wherein:

A is independently selected from N or C;

B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR¹,CCONH₂, CCH₃, C--R² or P; R¹ is independently H, lower alkyl, loweralkylamines, COCH₃, lower alkyl alkenyl, lower alkyl vinyl or loweralkyl aryls. R² is independently H, OH, halogens, CN, N₃, NH₂, C(═O)NH₂,C(═S)NH₂, C(═NH)NH₂.HCl, C(═NOH)NH₂, C(═NH)OMe, lower alkyl, loweralkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl arylsor substituted heterocycles;

D is independently selected from CH, CO, N, S, Se, O, NR¹, CCONH₂, CCH₃,C--R², P or nothing; R¹ is independently H, O, lower alkyl, loweralkylamines, COCH₃, lower alkyl alkenyl, lower alkyl vinyl or loweralkyl aryls. R² is independently H, OH, halogens, CN, N₃, NH₂, loweralkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, loweralkyl aryls or substituted heterocycles;

X is independently O, S, CH₂ or NR where R is COCH₃ ;

R₁ and R₄ are independently selected from H, CN, N₃, CH₂ OH, lower alkyland lower alkyl amines; and

R₂, R₃, R₅, R₆, R₇ and R₈ are independently selected from H, OH, CN, N₃,halogens, CH₂ OH, NH₂, OCH₃, NHCH₃, ONHCH₃, SCH₃, SPh, alkenyl, loweralkyl, lower alkyl amines and substituted heterocycles; such that

when R₂ ═R₃ ═H, then R₇ and R₈ are hydrogens or nothing.

when A═N; B═CO; C═N or NH; D═CO or C--NH₂ ; E is CH or C-substituted;F═CH; X═O, S or CH₂, then R₂ will not be H, OH, CH₃, halogens, N₃, CN,SH, SPh, CH₂ OH, CH₂ OCH₃, CH₂ SH, CH₂ F, CH₂ N₃, aryl, aryloxy orheterocycles.

when A═N; B═CO; C═N or NH; D═CO or C--N H₂ ; E is CH, C--CH₃ or halogen;F═CH; X═N--COCH₃, then R₂ will not be H or OH;

when A═N; B═CH; C═CH or CH₃ ; D═CH or C--CH₃ ; E is CH, C-- CH₃ or C--CONH₂ ; F═CH; X═O, or CH₂, then R₂ will not be H or OH;

when A═N; B═N, CO or CH; C═CH, C--Cl or C--OCH₃ ; D═CH or C--Ph; E isCH, C--Cl or C--Ph; F═N or CO; X═O, then R₂ will not be H or OH;

when A═N; B═CO or CS; C═N or NH; D═CO or C--N H₂ ; E is CH or N; F═N orCH; X═O, then R₂ will not be H or OH; and

when A═C; B═CH; C═NH; D═CO, CS or C--NH₂ ; E is N or NH; F═CO or CH;X═O, then R₂ will not be H or OH.

A particular class of compounds contemplated herein includes nucleosideanalogs having a ribofuranosyl moiety where the sugar has anL-configuration rather than the natural D-configuration. This classincludes compounds which contain modified natural nucleic acid basesand/or synthetic nucleoside bases like triazole, 3-cyano-1,2,4-triazole,methyl 1,2,4-triazole-3-carboxylate, 3-bromo-5-nitro-1,2,4-triazole,imidazole, 2-nitroimidazole,2-bromo-4(5)-aminoimidazole, pyrazole,3(5)-aminopyrazole-4-earboxamide, triazines, pyrrole, pyridine,azapyridine, thiazole, 1,2,5-thiadiazole, selenadiazole,4-amino-1,2,5-thiadiazole-3-carboxylic acid, methyl4-oxo(5H)-1,2,5-thiadiazole-3-carboxylate,4-amino-1,2,5-selenadiazole-3-carboxylic acid, tetrazole, azaphophole,4-amino-1,3-azaphosphole-5-carbonitrile,4-bromo-1,3-azaphosphole-5-crbonitrile, 2-aminophosphine-3-carbonitrile,methyl2-amino-3-cyano-phosphole-4-carboxylate,4,5-dicyano-1,3-diazaphophole,diazaphophole, isooxazole, 3-oxo(2H)-isothiazole-3-carboxylic acid,5-amino-3-chloroisothiazole-4-carbonitrile,5-methylthio-3-Oxo(2H)-isothiazole-4-carbonitrile, isothiazole,pyrimidine and other substituted derivatives of these bases. Compoundsof this class may also contain independently other hetero-monocyclicbases and their derivatives, certain modifications of the ribofuranosylmoiety, and both N- and C-linked L-nucleosides.

Especially preferred compounds in this class include L-Ribavirin,1-β-L-ribofuranosyl-1,2,4-triazole-3-carboxamide. L-Ribavirin isdescribed by FIG. 1 where A, B and E are nitrogen; C is C--C(O)NH₂ ; Dis nothing; F is CH; X is oxygen; R₁, R₄, R₅, R₇ and R₈ are hydrogens;and R₂, R₃, and R₆ are hydroxyl.

Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is amonocyclic synthetic D-nucleoside that has been demonstrated activityagainst variety of viral diseases (Huffman et al, Antimicrob. AgentsChemother., 3, 235, 1975; Sidwell et al, Science, 177, 705, 1972) andcurrently undergoing clinical trials in combination with γ-interferonfor the treatment of Hepatitis C virus. In the past two decades, avariety of Ribavirin D-nucleoside analogs have been explored and many ofthem exhibit the exceptional antiviral and antitumor activities.However, no work has been reported on the synthesis of L-isomer ofRibavirin analogs and their biological activity. In single crystal X-rayanalysis Ribavirin resemble structurally to guanosine (Prusiner et al.,Nature, 244, 116, 1973). Because of the resemblance of Ribavirin toguanosine, we expected that Ribavirin nucleoside analogs should showsimilar or superior immuno-modulating activity than guanosine analogs(Robins et al, U.S. Pat. No. 5,041,426) in addition to the antiviralactivity.

Uses

It is contemplated that the compounds of the present invention will usedto treat a wide variety of conditions, and in fact any condition whichresponds positively to administration of one or more of the compounds.Among other things it is specifically contemplated that compounds of theinvention may be used to treat an infection, an infestation, a cancer ortumor or an autoimmune disease.

Infections contemplated to be treated with the compounds of the presentinvention include respiratory syncytial virus (RSV), hepatitis B virus(HBV), hepatitis C virus (HCV), herpes simplex type I and 2, herpesgenitalis, herpes keratitis, herpes encephalitis, herpes zoster, humanimmunodeficiency virus (HIV), influenza A virus, hantann virus(hemorrhagic fever), human papilloma virus (HPV), measles and fungus.

Infestations contemplated to be treated with the compounds of thepresent invention include protozoan infestations, as well as helminthand other parasitic infestations.

Cancers or tumors contemplated to be treated include those caused by avirus, and the effect may involve inhibiting the transformation ofvirus-infected cells to a neoplastic state, inhibiting the spread ofviruses from transformed cells to other normal cells and/or arrestingthe growth of virus-transformed cells.

Autoimmune and other diseases contemplated to be treated includearthritis, psoriasis, bowel disease, juvenile diabetes, lupus, multiplesclerosis, gout and gouty arthritis), rheumatoid arthritis, rejection oftransplantation, allergy and asthma.

Still other contemplated uses of the compounds according to the presentinvention include use as intermediates in the chemical synthesis ofother nucleoside or nucleotide analogs which are, in turn, useful astherapeutic agents or for other purposes.

In yet another aspect, a method of treating a mammal comprisesadministering a therapeutically and/or prophylactically effective amountof a pharmaceutical containing a compound of the present invention. Inthis aspect the effect may relate to modulation of some portion of themammal's immune system, especially modulation of lymphokines profiles ofTh1 and Th2. Where modulation of Th1 and Th2 lymphokines occurs, it iscontemplated that the modulation may include stimulation of both Th1 andTh2, suppression of both Th1 and Th2, stimulation of either Th1 or Th2and suppression of the other, or a bimodal modulation in which oneeffect on Th1/Th2 levels (such as generalized suppression) occurs at alow concentration, while another effect (such as stimulation of eitherTh1 or Th2 and suppression of the other) occurs at a higherconcentration.

In general, the most preferred uses according to the present inventionare those in which the active compounds are relatively less cytotoxic tothe non-target host cells and relatively more active against the target.In this respect, it may also be advantageous that L-nucleosides may haveincreased stability over D-nucleosides, which could lead to betterpharmacokinetics. This result may attain because L-nucleosides may notbe recognized by enzymes, and therefore may have longer half-lives.

It is contemplated that compounds according to the present inventionwill be administered in any appropriate pharmaceutical formulation, andunder any appropriate protocol. Thus, administration may take placeorally, parenterally (including subcutaneous injections, intravenous,intramuscularly, by intrasternal injection or infusion techniques), byinhalation spray, or rectally, topically and so forth, and in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles.

By way of example, it is contemplated that compounds according to thepresent invention can be formulated in admixture with a pharmaceuticallyacceptable carrier. For example, the compounds of the present inventioncan be administered orally as pharmacologically acceptable salts.Because the compounds of the present invention are mostly water soluble,they can be administered intravenously in physiological saline solution(e.g., buffered to a pH of about 7.2 to 7.5). Conventional buffers suchas phosphates, bicarbonates or citrates can be used for this purpose. Ofcourse, one of ordinary skill in the art may modify the formulationswithin the teachings of the specification to provide numerousformulations for a particular route of administration without renderingthe compositions of the present invention unstable or compromising theirtherapeutic activity. In particular, the modification of the presentcompounds to render them more soluble in water or other vehicle, forexample, may be easily accomplished by minor modifications (saltformulation, esterification, etc.) which are well within the ordinaryskill in the art. It is also well within the ordinary skill of the artto modify the route of administration and dosage regimen of a particularcompound in order to manage the pharmacokinetics of the presentcompounds for maximum beneficial effect in patients.

In certain pharmaceutical dosage forms, the pro-drug form of thecompounds, especially including acylated (acetylated or other)derivatives, pyridine esters and various salt forms of the presentcompounds are preferred. One of ordinary skill in the art will recognizehow to readily modify the present compounds to pro-drug forms tofacilitate delivery of active compounds to a target site within the hostorganism or patient. One of ordinary skill in the art will also takeadvantage of favorable pharmacokinetic parameters of the pro-drug forms,where applicable, in delivering the present compounds to a targeted sitewithin the host organism or patient to maximize the intended effect ofthe compound.

In addition, compounds according to the present invention may beadministered alone or in combination with other agents for the treatmentof the above infections or conditions. Combination therapies accordingto the present invention comprise, the administration of at least onecompound of the present invention, or a functional derivative thereof,and at least one other pharmaceutically active ingredient. The activeingredient(s) and pharmaceutically active agents may be administeredseparately or together and when administered separately this may occursimultaneously of separately in any order. The amounts of the activeingredient(s) and pharmaceutically active agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect. Preferably the combination therapyinvolves the administration of one compound of the present invention ora physiologically functional derivative thereof and one of the agentsmentioned herein below.

Examples of such further therapeutic agents include agents that areeffective for the modulation of immune system or associated conditionssuch as AZT, 3TC, 8-substituted guanosine analogs,2',3'-dideoxynucleosides, interleukin II, interferons such as(-interferon, tucaresol, levamisole, isoprinosine and cyclolignans.Certain compounds according to the present invention may be effectivefor enhancing the biological activity of certain agents according to thepresent invention by reducing the metabolism or inactivation of othercompounds and as such, are co-administered for this intended effect.

With respect to dosage, one of ordinary skill in the art will recognizethat a therapeutically effective amount will vary with the infection orcondition to be treated, its severity, the treatment regimen to beemployed, the pharmacokinetics of the agent used, as well as the patient(animal or human) treated. Effective dosages may range from 1 mg/kg ofbody weight, or less, to 25 mg/kg of body weight or more. In general atherapeutically effective amount of the present compound in dosage formusually ranges from slightly less than about 1 mg./kg. to about 25mg./kg. of the patient, depending upon the compound used, the conditionor infection treated and the route of administration. This dosage rangegenerally produces effective blood level concentrations of activecompound ranging from about 0.04 to about 100 micrograms/cc of blood inthe patient. It is contemplated, however, that an appropriate regimenwill be developed by administering a small amount, and then increasingthe amount until either the side effects become unduly adverse, or theintended effect is achieved.

Administration of the active compound may range from continuous(intravenous drip) to several oral administrations per day (for example,Q.I.D.) and may include oral, topical, parenteral, intramuscular,intravenous, sub-cutaneous, transdermal (which may include a penetrationenhancement agent), buccal and suppository administration, among otherroutes of administration.

To prepare the pharmaceutical compositions according to the presentinvention, a therapeutically effective amount of one or more of thecompounds according to the present invention is preferably intimatelyadmixed with a pharmaceutically acceptable carrier according toconventional pharmaceutical compounding techniques to produce a dose. Acarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral. Inpreparing pharmaceutical compositions in oral dosage form, any of theusual pharmaceutical media may be used. Thus, for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives including water, glycols, oils, alcohols,flavouring agents, preservatives, colouring agents and the like may beused. For solid oral preparations such as powders, tablets, capsules,and for solid preparations such as suppositories, suitable carriers andadditives including starches, sugar carrier, such as dextrose, mannitol,lactose and related carriers, diluents, granulating agents, lubricants,binders, disintegrating agents and the like may be used. If desired, thetablets or capsules may be enteric-coated or sustained release bystandard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater or aqueous sodium chloride solution, though other ingredientsincluding those which aid dispersion may be included. Of course, wheresterile water is to be used and maintained as sterile, the compositionsand carriers must also be sterilized. Injectable suspensions may also beprepared, in which case appropriate liquid carriers, suspending agentsand the like may be employed.

Test Results

In vitro and in vivo tests on a compound of Formula I, L-Ribavirin, wereperformed, and the results are described below.

In a first series of experiments, peripheral blood mononuclear cells(PBMCs) were isolated from the buffy coat following Ficoll-Hypaquedensity gradient centrifugation of 60 ml blood from healthy donors.T-cells were then purified from the PBMCs using Lymphokwik lymphocyteisolation reagent specific for T-cells (LK-25T, One Lambda, Canoga ParkCalif.). An average yield of 40-60×10⁶ T-cells were then incubatedovernight at 37° C. in 20-30 ml RPMI-AP5 (RPMI-1640 medium (ICN, CostaMesa, Calif.) containing 20 mM HEPES buffer, pH 7.4, 5% autologousplasma, 1% L-glutamine, 1% penicillin/streptomycin and 0.05%2-mercaptoethanol) to remove any contaminating adherent cells. In allexperiments, T-cells were washed with RPMI-AP5 and then plated on96-well microtitre plates at a cell concentration of 1×10⁶ cells/ml.

The T-cells were activated by the addition of 500 ng ionomycin and 10 ngphorbol 12-myristate 13-acetate (PMA) (Calbiochem, La Jolla, Calif.) andincubated for 48-72 h at 37 ° C. PMA/ionomycin-activated T-cells weretreated with 0.5-50 μM of either Ribavirin (D-Ribavirin) or L-Ribavirin,or with 250-10000 U/ml of a control antiviral, interferon-alpha(Accurate, Westbury, N.Y.) immediately following activation andre-treated 24 h later. T-cells from each plate were used forimmunofluorescence analysis and the supernatants used for extracellularcytokine measurements. Following activation, 900 μl cell supernatantfrom each microplate was transferred to another microplate for analysisof cell-derived cytokine production. The cells are then used inimmunofluorescence analyses for intracellular cytokine levels andcytokine receptor expression.

Cell-derived human cytokine concentrations were determined in cellsupernatants from each microplate. Activation-induced changes ininterleukin-2 (IL-2) levels were determined using a commerciallyavailable ELISA kit (R & D systems Quantikine kit, Minneapolis, Minn.)or by bioassay using the IL-2-dependent cell line, CTLL-2 (ATCC,Rockville, Md.). Activation -induced changes in interleukin-4 (IL-4),tumor necrosis factor (TNFα) interleukin-8 (IL-8) (R & D systems(Quantikine kit, Minneapolis, Minn.) and interferon-gamma (IFN-γ)(Endogen (Cambridge, Mass.) levels were determined using ELISA kits. AllELISA results were expressed as pg/ml and the CTLL-2 bioassay as countsper minute representing the IL-2-dependent cellular incorporation of ³H-thymidine (ICN, Costa Mesa, Calif.) by CTLL-2 cells.

Comparison of the effects of D-Ribavirin and L-Ribavirin (expressed as apercentage of activated control) on IL-2 TNFα, IFN-γ, IL-4 and IL-5levels are presented in FIGS. 13 and 14.

In another set of experiments the effects of L-Ribavirin on theinflammatory ear response to dinitrofluorobenzene were determined. Theresults of those experiments are shown in FIG. 15.

Synthesis

The compounds according to the present invention may be producedaccording to synthetic methods which are individually readily known tothose of ordinary skill in the art. In general, compounds according tothe present invention are synthesized by condensing appropriatenucleoside base with the necessary sugar synthon to give the protectedL-nucleoside which on further manipulation and deprotection of the sugarhydroxyl protecting groups will ultimately give rise to nucleosideanalog having the desired ribofuranosyl moiety of the L-configuration.

During chemical synthesis of the various compositions according to thepresent invention, one of ordinary skill in the art will be able topractice the present invention without undue experimentation. Inparticular, one of ordinary skill in the art will recognize the varioussteps that should be performed to introduce a particular substituent atthe desired position of the base or a substituent at the desiredposition on the sugar moiety. In addition, chemical steps which aretaken to protect functional groups such as hydroxyl or amino groups,among others, as well as de-protected these same functional groups, willbe recognized as appropriate within the circumstances of the syntheses.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting. It will beunderstood by one of ordinary skill in the art that these examples arein no way limiting and that variations of detail can be made withoutdeparting from the spirit and scope of the present invention.

Compounds of The present invention may be prepared in accordance withwell known procedures in the art. Particularly useful are the followingsynthetic schemes.

Scheme 1: Synthesis of ribofuranosyl (R1, R4, R5, R7 and R8, arehydrogens; R2, R3 and R6 are hydroxyl) nucleosides of formula (II):Triazole L-ribofuranosyl nucleosides were prepared by the acid catalyzedfusion procedure (Sato, T., et al, Nippon Kagaku Zasshi, 81, 1440,1960). Accordingly, the triazoles (1) were mixed with1,2,3,5-tetra-O-acetyl-L-ribose (2) and a catalytic amount ofbis(p-nitrophenyl)phosphate and heated at 160-165 C for 30 min underreduced pressure to provide the required nucleosides which on furtherdeprotection furnished the triazole L-ribonucleosides (3) of formula(II). ##STR7##

Scheme 2: Synthesis of L-ribofuranosyl (R1, R4, R5, R7 and R8, arehydrogens; R2, R3 and R6 are hydroxyl) nucleosides of formula (III):Triazole, pyrazole and other 5-membered heterocyclic L-ribofuranosylnucleosides of the present invention were prepared by using Vorbruggenprocedure involves the treatment of the heterocycles (4) withchlorotrimethylsilane to provide the silyl intermediate which oncondensation with the protected ribose (5) in the presence of stannicchloride in an inert solvent affords the required nucleosides (6). Aftercondensation the products are deprotected by conventional methods knownto those skilled in the art, into compounds of the formula (III).##STR8##

Most of compounds of the formula (III) can be prepared by using theabove condensation procedure. The required1,2,3,5-tetra-O-acetyl-L-ribose and1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribose were prepared as shown inExample 2 and Example 13 respectively. The hetero monocyclic bases arecommercially available from Aldrich, Fluka, ICN, Acros, Alfa, Lancasterand TCI America or were prepared by following the reported procedurethat are available in the literature articles (Robins, R. K., et al,Nucleosides & Nucleotides, 13, 17-76, 1994). The preparation pyrrole,pyrazole and other type triazole L-nucleosides of formula (IV) wereachieved by following the procedures reported for the preparation of thecorresponding D-nucleosides in Chemistry of Nucleosides and Nucleotides,Edited by Leroy B. Townsend, New York, Plenum Press, 3, 1-105, 1994.Various imidazole L-nucleosides were prepared by following the reported(Shaw, G., in Chemistry of Nucleosides and Nucleotides, Edited by LeroyB. Townsend, New York, Plenum Press, 3, 263-420, 1994) methods toimidazole D-nucleosides.

Scheme 3: The compounds of formula (I) could be obtained by reacting theheterocycles (7) with L-ribose (5) by following the Vorbruggen procedure(Niedballa, U., et al, J. Org. Chem., 39, 3654, 1974) described abovefor the preparation of compounds of formula (III). ##STR9##

The C-nucleosides (where A is carbon in formulas I & III) ofL-configuration were prepared by exemplifying the procedure reported(Watanabe, K. A., in Chemistry of Nucleosides and Nucleotides, Edited byLeroy B. Townsend, New York, Plenum Press, 3, 421-535, 1994) for thepreparation their corresponding C-nucleosides of D-configuration.

Scheme 4: Preparation of L-arabinofuranosyl nucleosides (R₁, R₂, R₄, R₅and R₈ are hydrogens; R₃, R₆ and R₇ are hydroxyl): The b-anomers of thearabinosyl L-nucleosides of formulae (I-III) may be prepared by reacting2,3,5-tri-O-benzyl-L-arabinofuranosyl bromide (9; Baker, R., et al., J.Org. Chem., 26, 4605-4609, 1961) and the trimethylsilyl derivative ofthe base to give the intermediate L-nucleoside (10). Removal of theblocking groups of 10 should afford the required b-L-arabinofuranosylnucleosides. In the case of pyrrole b-L-arabinonucleosides the sodiumsalt glycosylation procedure (Revankar, G. R., et al, Nucleosides &Nucleotides, 6, 261-264, 1987) was followed. ##STR10##

Scheme 5: Preparation of L-xylofuranosyl nucleosides (R₁, R₃, R₄, R₅ andR₇ are hydrogens; R₂, R₆ and R₈ are hydroxyl): The b-anomers of thexylofuranosyl L-nucleosides of formulae (I-III) may be prepared from1,2-di-O-acetyl-3,5-di-O-benzyl-L-xylofuranose (11; Gosselin, G., etal., J. Heterocyclic Chem., 30, 1229-1233, 1993) and the appropriatebase, by following the method analogous to that described in scheme 4.##STR11##

Scheme 6: Preparation of L-2'-deoxyribofuranosyl nucleosides (R₁, R₂,R₄, R₅, R₇ and R₈ are hydrogens; R₃ and R₆ are hydroxyl): The b-anomersof the 2'-deoxyribofuranosyl L-nucleosides of formulae (I-III) may beprepared by reacting3',5'-Di-O-p-toluyl-2'-deoxyerythro-b-L-pentofuranosyl chloride (13)(Smejkal, J., et al, Collect. Czec. Chem. Commun. 29, 2809-2813, 1964)with the silyl derivative of the heterocycles in the presence ofBronsted acid to give exclusively the b-isomers (14) in good yield(Fujimori, S., et al, Nucleosides & Nucleotides, 11, 341-349, 1992;Aoyama, H., Bull. Chem. Soc., 60, 2073, 1987). The sameb-L-2'-deoxyribofuranosyl nucleosides were also prepared by the reactingthe chloro sugar (13) with sodium salt of the base (Kazimierczuk, Z., etal, J. Amer. Chem. Soc., 106, 6379-6382, 1984) in dry acetonitrile. Theintermediate (14) on treatment with methanolic ammonia provided therequired b-L-2'-deoxyerythro-pentofuranosyl nucleosides. ##STR12##

Scheme 7: Preparation of L-3'-deoxyribofuranosyl nucleosides (R₁, R₃,R₄, R₅, R₆, R₇ and R₈ are hydrogens; R₂ and R₆ are hydroxyl): Theb-anomers of the 3'-deoxyribofuranosyl L-nucleosides of formulae (I-III)may be prepared by reacting1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentose (15) with thesilyl derivative of the heterocycles in the presence of Lewis acid togive the b-isomers (16), which on deblocking with methanolic ammoniashould give b-L-3'-deoxyerythro-pentofuranosyl nucleosides. The samecompounds could also be prepared by reacting the corresponding 1-chloroderivative of (15) with sodium salt of the heterocyclic base, as in thecase of 2'-deoxy L-nucleosides described in scheme 6. ##STR13##

Scheme 8: Preparation of L-2',3'-dideoxyribofuranosyl nucleosides (R₁,R₂, R₃, R₄, R₅, R₇ and R₈ are hydrogens; R₆ is hydroxyl): The b-anomersof the 2',3'-dideoxyribofuranosyl L-nucleosides of formulae (I-III) maybe prepared by the treatment of their corresponding5'-O-triphenylmethyl-2',3'-bis(methanesulfonate)-b-L-ribofuranosylnucleosides (17) with sodium hydrogentelluride (Clive, D. L., et al, J.Org. Chem., 61, 7426-7437, 1996) in CH₃ CN at room temperature as shownbelow. Finally the trityl group will be removed from (18) under mildcondition to provide the 2',3'-dideoxyribofuranosyl b-L-nucleosides.##STR14##

Furthermore, substituted sugars such as1-bromo-2-deoxy-2-fluoro-3,6-O-benzoyl-L-arabinofuranose (Ma, T., et al,J. Med. Chem., 39, 2835-2843, 1996) and other modified sugars ofL-configuration are known in U.S. Pat. No. 5,473,063; WO 96/13512; WO96/13498; WO 96/22778; WO 95/20595; U.S. Pat. No. 5,473,063; U.S. Pat.No. 5,567,688; WalczaK, K., et al, Monatsh. fur Chemie, 123,349-354(1992); Wengel, J., et al, J. Org. Chem., 56, 3591-3594(1991);Genu-Dellac, C., et al, Tetrahedron Letts., 32, 79-82(1991) andCzernecki, S., et al, Synthesis, 783(1991). In addition, preparation ofmodified sugars and nucleosides of D-configuration are described in U.S.Pat. No. 5,192,749; WO 94/22890; Uteza, V., et al, Tetrahedron, 49,8579-8588(1993); Thrane, H., et al, Tetrahedron, 51, 10389-10403(1995);Yoshimura, Y., et al, Nucleosides & Nucleotides, 14, 427-429 (1993;Lawrence, A. J., et al, J. Org. Chem., 61, 9213-9222(1996); Ichikawa,S., et al, J. Org. Chem., 62, 1368-1375(1997); EP 0 457 326 A1; U.S.Pat. No. 3,910,885; WO 96/13498 and Karpeisky, M,Y., et al, NucleicAcids Res. Symposium Series, 9, 157 (1981). By applying the syntheticprocedures (schemes) that has been described in these articles for thepreparation of D-nucleosides, the corresponding modified L-nucleosidescould also be achieved.

Other compounds within the scope of the invention can be synthesizedusing the teachings of the schematics provided herein, as well as thespecific examples and other schemes set forth below. In addition to theteachings provided herein, the skilled artisan will readily understandhow to make compounds within the scope of the present invention byapplying well known techniques such as those described in Nucleic AcidChemistry, Improved and New Synthetic Procedures, Methods andTechniques, Edited by Leroy B. Townsend and R. Stuart Tipson, John Wiley& Sons, New York (1978-1991); Chemistry of Nucleosides and Nucleotides,Edited by Leroy B. Townsend, New York, Plenum Press (1988-1994) andNucleosides and Nucleotides as Antitumor and Antiviral Agents, Edited byChung K. Chu and David C. Baker, New York, Plenum Press (1993). Suitablemethods for making substitution within the sugar moiety of the presentlyclaimed compounds are known to those skilled in the art and aredescribed in various publications including: U.S. Pat. No. 5,559,101;U.S. Pat. No. 5,192,749; U.S. Pat. No. 5,473,063; U.S. Pat. No.5,565,438. Suitable methods for making various heterocyclic compoundsand substitution on them are provided in Chemistry of Nucleosides andNucleotides, Edited by Leroy B. Townsend, New York, Plenum Press, 2,161-398 (1991) and Chemistry of Nucleosides and in Nucleotides, Editedby Leroy B. Townsend, New York, Plenum Press, 3, 1-535 (1994).

EXAMPLES

The invention can be further understood by referring to the followingexamples below, wherein the compound numerals in bold correspond to likenumbered numerals in FIGS. 1-12.

Example 1 1-O-Methyl-2,3,5-Tri-O-acetyl-β-L-ribofuranose (19)

L-Ribose (15.0 g, 100 mmol) was dissolved in dry methanol (200 mL) andcooled to 0 ° C. To this cold stirred solution H₂ SO₄ (2 mL) was addedslowly and the reaction mixture stirred at below 20° C. for 12 h underargon atmosphere. Dry pyridine (75 mL) was added and evaporated todryness. Dry pyridine (100 mL) was added and evaporated under reducedpressure to an oily residue. This residue was dissolved in dry pyridine(150 mL) and treated with acetic anhydride (50 mL) at 0° C. under argonatmosphere. TEA (41 mL) was added, the reaction stirred at 0° C. for 1 hand at room temperature for 36 h, evaporated to dryness. The residue wasdissolved in water (200 mL), solid NaHCO₃ was added slowly to adjust thepH of the solution to 7. The aqueous mixture was extracted in CH₂ Cl₂(250 mL), washed with water (150 mL) and brine (100 mL), dried andconcentrated. The oily residue was filtered on a bed of silica gel (200g), washed with CH₂ Cl₂ :EtOAc (8:2, 1000 mL). The filtrate wasevaporated and the oil was used as such for the next reaction.

Example 2 1,2,3,5-Tetra-O-acetyl-β-L-ribofuranose (2)

The syrup (19) (29.0 g, 100 mmol) from the above reaction wasco-evaporated with dry toluene (2×100 mL) and dried overnight undersolid NaOH at room temperature in vacuo. The dried syrup was dissolvedin glacial acetic acid (150 mL) and cooled to 0° C. under argonatmosphere. To this cold solution was added acetic anhydride (35 mL)followed by H₂ SO₄ (10 mL) very slowly during 15 minute period. Thereaction mixture was stirred at room temperature overnight and pouredinto ice (200 g) with stirring. The mixture was extracted with CHCl₃(2×200 mL) and the organic extract was washed with water (200 mL), sat.NaHCO₃ (200 mL) and brine (150 mL), dried over anhydrous Na₂ SO₄ andevaporated to dryness. The syrup 30 g (94%) that obtained was found tobe pure enough for glycosylation reactions.

Example 3A

Methyl1-(2,3,5-Tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate(20)

A mixture of methyl 1,2,4-triazole-3-carboxylate (0.64 g, 5 mmol),1,2,3,5-tetra-O-acetyl-β-L-ribofuranose (2) (1.5 g, 4.72 mmol) andbis(p-nitrophenyl)-phosphate (20 mg) were placed in a pear shaped flaskand placed in a preheated oil bath at (160-165° C.). The flask wasconnected to a water aspirator and kept at 160-165° C. (oil bathtemperature) under reduced pressure with stirring for 25 min. Thereaction mixture was removed, cooled and diluted with EtOAc (150 mL) andsat. NaHCO₃ (100 mL). The product was extracted in EtOAc. The organicextract was washed with water (100 mL) and brine (50 mL), dried andevaporated to dryness. The residue that obtained was purified by flashcolumn of silica gel using CHCl₃ →EtOAc as the eluent. The purefractions were collected and evaporated to dryness to give 1.2 g (66%)of pure product: ¹ H NMR (CDCl₃) δ 2.10 (3s, 9H, 3 COCH₃), 3.98 (s, 3H,OCH₃), 4.22 (m, 1H), 4.46 (m, 2H), 5.54 (t, 1H), 5.76 (m, 1H), 6.04 (d,1H, C_(1'),), and 8.38 (s, 1H, C₃ H). Anal. Calc. for C₁₅ H₁₉ N₃ O₉(385.22): C, 46.75; H, 4.97; N,10.91. Found: C, 46.82; H, 4.57; N=10.71.

Example 3B 1-β-L-Ribofuranosyl-1,2,4-triazole-3-carboxamide (21)

The substrate (20) (1.1 g) was dissolved in CH₃ OH/NH₃ at 0° C. andplaced in a steel bomb. The bomb was closed and stirred at roomtemperature for 18 h. The steel bomb was cooled, opened and evaporatedto dryness. The residue was tried to crystallization with littleethanol. The product crystallized, but on filtration, the crystalsre-absorbed water and became a paste. The crystallization repeatedseveral times. Finally it crystallized from Methanol/Ethanol mixture.The colorless crystals was filtered, washed with methanol and dried invacuo. The filtrate was evaporated again which on standing gave furthercrystals. Total yield 0.5 g (72%); mp: 177-179° C.; [a]_(D) =+38.33 (c 3mg/mL H₂ O); D form of Ribavirin [a]_(D) =-36.0 (c 3.0 mg/mL H₂ O); ¹ HNMR (Me₂ SO-d₆) δ 3.46 (m, 1H, C_(5') H), 3.60 (m, 1H, C₅ h), 3.92 (q,1H, C₄ H), 4.12 (q, 1H), 4.34 (q, 1H), 4.88 (t, 1H, C_(5') OH), 5.20 (d,1H), 5.58 (d, 1H), 5.80 (d, 1H, C_(1') H), 7.60 (bs, 1H, NH), 7.82 (bs,1H, NH), and 8.82 (s, 1H, C₃ H). Anal. Calc. for C₈ H₁₂ N₄ O₅ (244.20):C, 39.34; H, 4.95; N, 22.94. Found: C, 39.23; H, 4.97; N, 22.91.

Example 4 2,3-O-Isopropylidene-L-ribose (22)

To a stirred suspension of L-ribose (30.0 g, 260 mmol) in dry acetone(200 mL) was added iodine (1.27 g, 10 mmol) at room temperature underargon atmosphere. The reaction mixture was stirred for 1 h (the solutionbecomes homogeneous during this period) and quenched with sodiumthiosulfate solution (1 M). The solution was evaporated to dryness. Theresidue was dissolved in CH₂ Cl₂ (250 mL), dried over anhydrous MgSO₄,filtered and the solid was washed with CH₂ Cl₂ (150 mL). The combinedfiltrate was evaporated to dryness. The residue was placed on top ofsilica column (8×116 cm) packed in CHCl₃. The column was eluted withCHCl₃ (500 mL), CHCl₃ :EtOAc (9:1, 1000 mL) and CHCl₃ : EtOAc (7.3. 1500mL). The pure product eluted in CHCl₃ : EtOAc (7:3) was collected andevaporated to give an oily residue 34.5 g (90%). The oily product usedas such for the next reaction. ¹ H NMR (CDCl₃) δ 1.30 and 1.38 (2s, 6H,isopropylidene CH₃), 3.70 (m, 3H), 4.08 (m, 1H), 4.38 (m, 1H), 4.55 (d,1H), 4.81 (d, 1H) and 5.38 (m, 1H).

Example 5 1-Deoxy-1-hydrazinyl-2,3-O-isopropylidene-L-ribose (23)

A solution of 2,3-O-isopropylidene-L-ribose 22 (34.5 g, 182 mmol) inabsolute methanol (200 mL) was treated with a solution of anhydroushydrazine (42.0 g, 1313 mmol) in absolute methanol (100 mL) drop-wiseover a period of 30 min and at room temperature under argon atmosphere.The nearly colorless solution was stirred at room temperature and underanhydrous condition for 18 h. The solution was evaporated in vacuo toafford a colorless syrup. The syrup was repeatedly co-evaporated withabsolute methanol (5×100 m). The resulting syrup was momentarily warmed(70° C.) under vacuum pump pressure (0.1 torr) and then kept at thispressure for drying for 12 h. The yield was 35.0 g (95%). This materialwas used as such without further purification for the next step.

Example 65-Amino-4-cyano-1-(2',3'-O-isopropylidene-β-L-ribofuranosyl)pyrazole(24)

A solution of 1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-L-ribose (23)(16.3 g, 79.90 mmol) in absolute ethanol (100 mL) was purged with asteady stream of argon for 30 min. A similarly purged solution of(ethoxymethylene)-malanonitrile (10.37 g, 85 mmol) in absolute ethanol(100 mL) was added drop-wise to the rapidly stirred solution at roomtemperature during a 1 h period. The solution was stirred under argonfor an additional 30 min and then heated at reflux for 12 h. The orangesolution was cooled to room temperature and evaporated in vacuo todryness. This material was dissolved in ethyl acetate (100 mL) and thentreated with silica gel (50 g). The mixture was evaporated to dryness invacuo and the powder which resulted was applied to the top of a silicagel (500 g) column (6×30 cm, dry packed). The column was eluted withgradient of CH₂ Cl₂ →EtOAc solvent. Fractions having the pure productwere pooled together and evaporated to a foam: Yield 17 g (76%); ¹ H NMR(CDCl₃) δ 1.30 and 1.52 (2s, 6H, isopropylidene CH₃), 3.86 (m, 2H,C_(5') H), 4.40 (m, 1H, C_(4') H), 4.80 (bs, 2H, NH₂), 5.00 (d, 1H),5.20 (m, 1H), 5.80 (d, 1H, C_(1') H) and 7.54 (bs, 1H, C₃ H). Anal.Calc. for C₁₂ H₁₆ N₄ O₄ (280.28): C, 51.43; H, 5.75; N, 19.99. Found: C,51.20; H, 5.63; N, 19.98.

Example 7 5-Amino-1-(β-L-ribofuranosyl)pyrazole-4-carbonitrile (25)

A solution of5-amino-1-(2',3'-O-isopropylidene-β-L-ribofuranosyl)-pyrazole-4-carbonitrile(24) (4.6 g, 16.43 mmol) in 90% trifluoroacetic acid (30 mL) was stirredat room temperature for 4 h. The reaction mixture was evaporated todryness and the residue was co-evaporated with methanol (3×35 mL). Theresidue was used as such for further reactions.

Example 8 5-Amino-1-(β-L-ribofuranosyl)pyrazole-4-carboxamide (26)

To a solution of (25) (4.60 g) in ammonium hydroxide (35 mL) was added30% hydrogen peroxide (2 mL). The mixture was stirred in a pressurebottle at room temperature for 18 h, the pressure bottle was cooled,opened carefully and the volatile products were evaporated to dryness.The residue thus obtained was co-evaporated with ethanol (3×20 mL). Thecrude product on crystallization with ethanol/water gave pure compound3.5 g (71%): ¹ H NMR (DMSO-d₆) δ 3.57 (m, 2H, C_(5') CH₂), 3.86 (q, 1H,C_(4') H), 4.11 (q, 1H, C_(3') H), 4.43 (q, 1H, C_(2') OH), 5.63 (d, 1H,J=3.99 Hz, C_(1'),H), 6.51 (br s, 2H, NH₂), 6.71 and 7.26 (2br s, 2H,CONH₂) and 7.69 (s, 1H, C₃ H). Anal. Calc. for C₉ H₁₄ N₄ O₅ (258.23): C,41.86; H, 5.46; N, 21.69. Found: C, 41.57; H, 5.40; N, 21.61.

Example 95-Amino-1-(2',3'-O-isopropylidene-β-L-ribofuranosyl)pyrazole-3,4-dicarbonitrile(27)

A solution of tetracyanoethylene (24.32 g, 190 mmol) in absolute EtOH(100 mL) was added drop-wise with stirring to a solution of1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-L-ribose (223.0 g, 113.0 mmol)in EtOH (100 mL), over a period of 30 min at 0° C. The reaction mixturewas stirred at ice-bath temperature for an additional 2 h and thenstirred at room temperature for 15 h. The brown solution was filteredand evaporated to dryness. The residue was dissolved in MeOH (50 mL),adsorbed onto silica gel (90 g), and placed on top of a silica gelcolumn (10×25 cm) packed with CH₂ Cl₂. The column was eluted with CH₂Cl₂ /EtOAc (10:1, v/v); the homogeneous fractions were pooled andevaporated to dryness. The residual yellow foam was crystallized from aethanol on long standing at room temperature to yield 15 g (44%) of pure(27): mp ° C.; ¹ H NMR (Me₂ SO-d₆) δ 1.31 and 1.48 (2s, 6H,isopropylidene-CH₃), 3.29 (m, 2H, C_(5') CH₂), 4.13 (m, 1H, C_(4') H),4.83 (m, 1H, C_(3') H), 4.97 (t, 1H, C_(5') OH), 5.24 (m, 1H, C_(2') H),6.12 (s, 1H, C_(1') H), 7.65 (s, 2H, NH₂). Anal. Calc. for C₁₃ H₁₅ N₅ O₄(305.29): C, 51.14; H, 4.95; N, 22.94. Found: C, 51.20; H, 5.04; N,22.61.

Example 10 5-Amino-1-β-L-ribofuranosylpyrazole-3,4-dicarbonitrile (28)

A suspension of5-amino-1-(2',3'-O-isopropylidene-β-L-ribofuranosyl)-pyrazole-3,4-dicarbonitrile(4.6 g, 15.0 mmol) in 90% TFA/water (50 mL) was stirred at roomtemperature for 12 h. The solvent was evaporated and the residue wasco-evaporated with EtOH (3×50 mL). The light brown residue thus obtainedwas used as such for further reaction.

Example 11 5-Amino-1-β-L-ribofuranosylpyrazole-3,4-dicarboxamide(29)

The TFA salt of 5-amino-1-β-L-ribofuranosylpyrazole-3,4-dicarbonitrile(28) (2.60 g, 10.0 mmol) was dissolved in conc. NH₄ OH (28%, 100 mL) andtreated with H₂ O₂ (30%, 15 mL). The reaction mixture was stirred atroom temperature in a pressure bottle for 12 h, and then evaporated todryness. The residue was co-evaporated with MeOH (3×50 mL). The crudeproduct was crystallized from a mixture of EtOH/water to give 2.0 g(68%) of (29): mp×° C.; ¹ H NMR (Me₂ SO-d₆) δ 3.60 (m, 2H, C_(5') CH₂)3.87 (m, 1H, C_(4') H), 4.18 (m, 1H, C_(3') H), 4.54 (m, 1H, C_(2') H),4.91 (t, 1H, C₅,OH), 5.03 and 5.38 (2d, 2H, C_(2'),3' OH), 5.69 (d, 1H,C_(1') H), 6.99 (br s, 3H, NH₂ and CONH(H)), 7.72 and 7.78 (2s, 2H,CONH₂), and 9.65 (d, 1H, CON(H)H). Anal. Calc. for C₁₀ H₁₅ N₅ O₆(301.26): C, 39.87; H, 5.03; N, 23.25. Found: C, 39.72; H, 5.40; N,23.61.

Example 12 Dimethyl 1,2,3-triazole-4,5-dicarboxylate (30)

To a stirred suspension of sodium azide (5.03 g, 77.39 mmol) in DMF (120mL) was added dropwise at 0° C. over 30 min, a solution of dimethylacetylene-dicarboxylate (10.0 g, 70.36 mmol) in DMF (100 mL). After 30min the solvent was removed in vacuo at 30° C. to leave a lightpurple-brown solid. The solid was washed twice with ether and taken upin water (100 mL). The aqueous solution was acidified with conc. HCl topH 2. The aqueous layer was first extracted with ether (100 mL) and thenwith chloroform (100 mL). The combined organic layers were evaporated togive a light red colored solid: 128-130° C. The solid was washed withhot hexane and crystallized from benzene: Yield 11.0 g (85%); ¹ H NMR(CDCl₃) δ 4.00 (s, 6H), 11.87 (br s, 1H, NH).

Example 13 1-O-Acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (5)

To a solution of L-ribose (25.0 g, 166.66 mmol) in MeOH (300 mL), wasadded 25 mL of sat. methanolic hydrogen chloride and stirred at roomtemperature for 6 h. The reaction was complete after 6 h as indicated byTLC using CH₂ Cl_(2/) MeOH 9:1. After completion of the reaction, drypyridine (30 mL) was added and the solvents were evaporated. To theresidue another 30 mL of pyridine was added and evaporated to dryness.The residue was dissolved in dry pyridine (200 mL) and CH₂ Cl₂ (150 mL)then cooled to 0 ° C. Benzoyl chloride (96.26 mL, 830.12 mmol) was addeddrop-wise and stirred at room temperature overnight. TLC usinghexane/ethyl acetate (7:3), indicated completion of the reaction. Thesolvents were evaporated and the residue dissolved in CHCl₃ (300 mL),and washed with H₂ O (200 mL) and sat. NaHCO₃ (200 mL), and dried overanhydrous Na₂ SO₄. After evaporating the CHCl₃, the residue wasco-evaporated with toluene to give an oily residue. The residue wasdissolved in AcOH (200 mL), acetic anhydride (85.0 mL; 770.9 mmol) andsulfuric acid (4.46 mL; 83.29 mmol). The reaction mixture was stirred atroom temperature overnight, after which time TLC (hexane/ethyl acetate7:3) indicated completion of the reaction. The solvents were evaporatedin vacuo and the residue that obtained was co-evaporated with toluene.The brown residue was triturated with EtOH to give light brown crystals.Filtration of the solid and recrystallization from EtOH gave 1-O-acetyl-2,3,5-tri-O-benzoyl-L(+)-glucofuranose 40.5 g (48.0%) as whitecrystals: mp 125-125° C.; ¹ H NMR (CDCl₃) δ 4.49 (m, 1H, C_(5') H), 4.77(m, 2H, C_(4') H and C_(5') H), 5.80 (d, 1H), 5.93 (m, 1H, C_(2') H),6.43 (d, 1H, C_(1') H, J₁,2 =1.5 Hz) and 7.30-8.09 (m, 15H, PhH).

Example 14 Dimethyl2-(2',3',5'-tri-O-benzoyl-β-L-ribofuranosyl)-1,2,3-triazole-4,5-dicarboxylate(31)

A mixture of dry dimethyl 1,2,3-triazole-4,5-dicarboxylate (3.70 g, 20.0mmol), hexamethyldisilazane (HMDS, 60 mL), and (NH₄)₂ SO₄ (0.1 g) washeated under reflux (oil-bath temperature 140° C.) for 12 h with theexclusion of moisture. Excess HMDS was removed by distillation in vacuoto provide the trimethylsilyl derivative, which was dissolved inanhydrous CH₃ CN (100 mL).

To the above clear solution was added 1-O-acetyl 2,3,5tri-O-benzoyl-L-ribofuranose (10.12 g, 20 mmol) and the mixture wasstirred for 10 min. To this stirred solution was added trimethylsilyltrifluoromethanesulfonate (4.6 mL, 26.0 mmol) and the stirring wascontinued for 12 h at ambient temperature. The reaction mixture wasevaporated and the residue was dissolved in CH₂ Cl₂ (500 mL). Theorganic layer was washed successively with aqueous sat. NaHCO₃ solution(3×100 mL), sat. NaCl solution (3×100 mL), and water (3×50 mL) and driedover anhydrous Na₂ SO₄. The solvent was evaporated furnish 12.0 g (95%)of 31: ¹ H NMR (Me₂ SO-d₆) δ 3.88 (s, 6H, 2 OCH₃), 4.65 (m, 2H, C_(5')H), 5.01 (m, 1H, C_(4') H), 6.10 (m, 1H, C_(3') H), 6.32 (m, 1H, C_(2')H), 6.88 (d, 1H, C_(1') H, J₁,2 =2.75 Hz) and 7.45-7.95 (m, 15H, PhH).

Example 15 2-β-L-Ribofuranosyl-1,2,3-triazole-4,5-dicarboxamide (32)

Compound 31 (6.0 g, 9.5 mmol) was dissolved in MeOH/NH₃ (dry MeOH sat.with anhydrous NH₃ at 0° C., 60 mL) were placed in a steel reactionvessel. The vessel was heated at 95° C. for 16 h. The reaction vesselwas cooled, opened carefully and the NH₃ was allowed to evaporate atroom temperature. The MeOH was evaporated to dryness and the residue wastriturated with hot toluene (3×50 mL) and filtered. The brown residuewas crystallized from aqueous EtOH (95%) to furnish 2.40 g (89%) of 32:mp 210-212° C.; ¹ H NMR (Me₂ SO-d₆) δ 3.45-3.59 (m, 2H, C_(5') H), 3.98(m, 1H, C_(4') H), 4.25 (m, 1H, C_(3') H), 4.54 (m, 1H, C_(2') H), 4.78(t, 1H, C_(5') OH, D₂ O exchangeable), 5.27 and 5.67 (2d, 2H, C_(2'),3'OH, D₂ O exchangeable), 5.89 (d, 1H, J_(1'),2' =3.85 Hz, C_(1') H), 8.05and 9.05 (2br s, 4H, 2 CONH₂). Anal. Calc. for C₉ H₁₃ N₅ O₆ (287.23): C,37.63; H, 4.56; N, 24.38. Found: C, 37.52; H, 4.19; N, 24.59.

Example 161-(2',3',5'-Tri-O-benzoyl-β-L-ribofuranosyl)pyridine-4-one-3-carboxamide(33)

To a mixture of hexamethyldisilazane (50 mL, 239.77 mmol) andchlorotrimethylsilane (1.0 mL, 21.43 mmol) was addedpyridine-4-one-3-carboxamide (1.38 g, 10.0 mmol) (Prepared by theprocedure reported: W. C. J. Ross, J. Chem. Soc., C, 1816, (1966); W.Herz and D. R. K. Murty, J. Org. Chem., 26, 122, 1961). The mixture wasrefluxed with stirring for 2 h and then evaporated to dryness undervacuum and further dried under high vacuum for 2 h at 60° C. The drygummy residue was suspended in freshly distilled 1.2-dichlorethane (50mL) and to this suspension was added1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10.0 mmol) andfreshly distilled SnCl₄ (1.0 mL, 8.52 mmol). The reaction mixture wasrefluxed for 1.5 h, cooled and diluted with CH₂ Cl₂ (100 mL) and sat.aqueous NaHCO₃ (25 mL). The mixture was filtered through celite and thebed was washed with CH₂ Cl₂ (20 mL). The organic phase was separated,washed with water until the washings are neutral, dried over anhydroussodium sulfate. The organic extract was evaporated to dryness to give agummy residue. The residue was purified by flash chromatography oversilica gel using CH₂ Cl₂ →EtOAc as the eluent. Pure fractions werepooled and concentrated to provide 0.50 g (9%) of 33 as white foam: ¹ HNMR (CDCl₃): δ 4.94 (m, 3H, C_(4') H and C_(5') H), 6.12 (m, 1H), 6.20(m, 1H), 6.32 (d, 1H) and 7.20-8.30 (m, 20H).

Example 17 1-β-L-ribofuranosylpyridine-4-one-3-carboxamide (34)

Compound 33 (0.5 g, 0.86 mmol) was dissolved in dry methanolic ammonia(50 mL) and stirred for 15 h in a bomb at room temperature. The solutionis then concentrated to a small volume and cooled overnight at 4° C. Thecrystalline product formed was filtered off, washed with cold methanol.The solid was recyrstallized from absolute ethanol to give 0.23 g (87%)of pure product: mp 209-211° C.; ¹ H NMR (Me₂ SO-d₆) δ 3.60 (m, 2H,C_(5') H), 3.93 (m, 1H, C_(4') H), 4.09 (m, 1H, C_(3') H), 4.34 (m, 1H,C_(2') H), 5.11 (m, 1H, C_(5') OH, D₂ O exchangeable), 5.22 and 5.47(2m, 2H, C_(2'),3' OH, D₂ O exchangeable), 5.84 (d, 1H, J_(1'),2' =6.3Hz, C_(1') H), 7.21 (m, 2H, PhH), 7.64 (m, 2H, PhH and CONH₂) and 8.44(s, 1H, CONH₂). Anal. Calc. for C₁₁ H₁₄ N₂ O₆ (270.24): C, 48.89; H,5.22; N,10.37. Found: C, 48.89; H, 5.42; N, 10.51.

Example 18 2,3,5-Tri-O-benzoyl-β-L-ribofuranosyl Azide (35)

Dry hydrogen chloride was passed through a suspension of finely powderedand dried 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribose (20.0 g, 39.52 mmol)in ether (300 mL.) at 0° C. until a clear solution obtained (2-3 h). Themixture was then set aside at 0° C. overnight. The solvent was removedand the residual gum evaporated successively with dry benzene (2×25 mL.)and toluene (25 mL.). The residue was dissolved in methyl cyanide (250mL). To this was added sodium azide (20.0 g, 307.6 mmol) and thereaction mixture was refluxed under argon atmosphere for 2 h. After thecompletion of the reaction, as determined by TLC hexane/ethyl acetate(7:3), the solution was filtered and evaporated to give an oily product(14.6 g) in quantitative yield. The product gave a white foam under highvacuum drying. The dried material was used as such for further reaction.¹ H NMR (CDCl₃) δ 4.54 (m, 1H), 4.76 (m, 2H), 5.57-5.58 (dd, 1H), 5.68(d, 1H, J=1.65 Hz), 5.84-5.86 (m, 1H) and 7.34-8.12 (m, 15H, PhH).

Example 195-Amino-1-(2',3',5'-tri-O-acetyl-3-L-ribofuranosyl)triazole-4-carboxamide(36)

N,N-Dimethylformamide (60 mL) was added to a cold (0° C.) solution ofpotassium hydroxide (1.72 g, 30.7 mmol) in water (10 mL) and thesolution stirred at this temperature for 10 min. Cyanoacetamide (2.58 g,30.68 mmol) was added to this solution and the mixture was then stirredat 0° C. until all the solid material had dissolved. To this solutionwas added 2,3,5-tri-O-benzoyl-b-L-ribofuranosyl azide (10.0 g, 20.5mmol) in one portion, and the reaction was stirred at -5° C. for 14 h.The amber solution was evaporated in vacuo (water bath 50° C.) to affordan orange semisolid, which was successively co-evaporated with absoluteethanol (2×50 mL) and toluene (3×50 mL) in vacuo to afford a thickorange gum. The gum was dissolved in anhydrous methanol (150 mL), sodiummethoxide (1 N, 25 mL) was added and the solution was stirred at roomtemperature under anhydrous conditions for 6 h. The amber solution wastreated with Dowex 50 X H⁺ ion-exchange resin (ca. 35 mL wet resin) toadjust the pH to 6. The solution was filtered, the resin bed was washedwith an additional methanol (50 mL) and the combined filtrates wereevaporated to dryness in vacuo (water bath 80° C.) to yield an orangegum. The gum was repeatedly triturated with ethyl acetate (6×50 mL), andeach portion was in turn decanted until the gum solidified to a tanamorphous solid. The off-white crude product 2.5 g (32%) waschromatographically pure. After several crystallization the productcontained impurities it is converted to the acetate form as describedbelow.

The above crude material (0.4 g, 1.54 mmol) was dissolved in drypyridine (10 mL). The solution was cooled to 0° C. under argonatmosphere and treated with acetic anhydride (0.95 g, 9.26 mmol). Thereaction mixture was stirred at room temperature overnight and thequenched with methanol (1.0 mL). The solvent was removed and the residuedissolved in CH₂ Cl₂ (100 mL). The organic layer was washed with sat.NaHCO₃ (100 mL) and brine (50 mL), dried and evaporated to dryness. Thecrude product was purified by flash chromatography over silica gel usingEtOAc as the eluent: Yield 0.52 g (88%); ¹ H NMR (CDCl₃) δ 2.12 (3s, 9H,3 COCH₃), 4.32-4.52 (m, 3H), 5.64 (m, 1H, C_(3') H), 5.85 (m, 1H, C_(2')H), 6.00 (br s, 2H, NH₂), 6.32 (d, 1H, C_(1') H) and 8.73 (br s, 2H,CONH₂).

Example 20 5-Amino-1-β-L(+)-ribofuranosyltriazole-4-carboxamide (37)

Compound 36 (0.5 g, 1.29 mmol) was dissolved in methanolic ammonia (50mL, sat. at ° C.). The reaction mixture was stirred at room temperaturefor 16 h and evaporated to dryness. The residue was triturated thricewith EtOAc and the solid was crystallized from minimum amount of dryEtOH to yield colorless solid: mp 159-161° C.; ¹ H NMR (Me₂ SO-d₆) δ3.40-3.52 (m, 2H, C_(5') H), 3.93 (m, 1H, C_(4') H), 4.19 (m, 1H, C_(3')H), 4.46 (m, 1H, C_(2') H), 4.74, 5.22, 5.62 (m, 3H, 3 OH, D₂ Oexchangeable), 5.84 (d, 1H, J=3.90 Hz, C₁ H), 7.95 (br s, 2H) and 9.02(br s, 2H). Anal. Calc. for C₈ H₁₃ N₅ O₅ (259.22): C, 37.07; H, 5.05; N,27.02. Found: C, 37.36; H, 5.14; N, 27.01.

Example 215-O-Acetyl-1-(2',3',5'-tri-O-acetyl-β-L-ribofuranosyl)triazole-4-carboxamide(38)

N,N-Dimethylformamide (40 mL) was added to a cold (0° C.) solution ofpotassium hydroxide (1.16 g, 20.82 mmol) in water (20 mL), and thesolution stirred at this temperature for 10 min. Ethyl malonamate (2.73g, 20.82 mmol) was added to this solution, and the mixture was thenstirred at 0° C. until all of the solid material had dissolved. To thissolution was added 2,3,5-tri-O-benzoyl-β-L-ribofuranosyl azide (6.76 g,13.88 mmol) in one portion, and the reaction was stirred at -5° C. for14 h. The amber solution is evaporated in vacuo (water bath 80° C. toafford an orange semisolid, which was successively co-evaporated withabsolute ethanol (2×50 mL) and toluene (3×50 mL) in vacuo to afford athick orange gum. The gum was dissolved in anhydrous methanol (150 mL),sodium methoxide (0.5 N, 10 mL) was added and the solution was stirredat room temperature under anhydrous condition for 6 h. The ambersolution was treated with Dowex 50 X H⁺ ion-exchange resin (ca. 35 mLwet resin) to adjust the pH to 6. The solution was filtered, the resinbed was washed with an additional 50 mL of methanol, and the combinedfiltrates were evaporated to dryness in vacuo (water bath 80° C.) toyield an orange gum. The gum was repeatedly triturated with ethylacetate (6×50 mL), and each portion was in turn decanted until the gumsolidified to a tan amorphous solid. The solid was suspended inanhydrous pyridine (30 mL) and acetic anhydride (7.8 mL, 83.28 mmol),stirred under anhydrous conditions at room temperature for 18 h. Thereaction mixture was filtered through a shallow bed of packed Celite.The Celite bed was washed with fresh pyridine (50 mL) and the combinedfiltrates were evaporated to dryness in vacuo to yield a brown gum. Thegum was dissolved in CH₂ Cl₂ (150 mL). The organic layer was washed withsat. NaHCO₃ (100 mL) and brine (50 mL), dried and evaporated to dryness.The crude product was purified by flash chromatography over silica gelusing CH₂ Cl₂ →EtOAc as the eluent. Pure fractions were collected andevaporated to provide 1.5 g (42%) of pure product 38. ¹ H NMR (CDCl₃) δ2.14 (3s, 9H, 3 COCH₃), 2.60 (s, 3H, COCH₃), 4.15-4.58 (m, 3H, C_(4') Hand C_(5') H), 5.62 (m, 1H, C_(3') H), 5.82 (m, 1H, C_(2') H), 6.28 (d,1H, C_(1') H) and 10.63 (br s, 2H, CONH₂).

Example 22 5-Hydroxy-1-β-L(+)-ribofuranosyltriazole-4-carboxamide (39)

Compound 38 (1.5 g, 3.50 mmol) was dissolved in methanolic ammonia (50mL, saturated at ° C.). The reaction mixture was stirred at roomtemperature for 16 h and evaporated to dryness. The residue wastriturated thrice with EtOAc and the solid was crystallized from minimumamount of dry EtOH to yield 0.70 g (77%) of 39: mp 162-164° C.; ¹ H NMR(Me₂ SO-d₆) δ 3.40-3.50 (m, 2H, C_(5') h), 3.84 (m, 1H, C_(4') H), 4.17(m, 1H, C_(3') H), 4.32 (m, 1H, C_(2') H), 4.90 (t, 1H, C_(5') OH),5.20, 5.58 (2d, 2H, 2 OH, D₂ O exchangeable), 5.76 (d, 1H, J=3.90 Hz,C_(1') H), 7.58 and 7.80 (2br s, 2H, CONH₂) and 8.82 (s, 1H, C₅ OH).Anal. Calc. for C₈ H₁₂ N₄ O₆ (260.21): C, 36.92; H, 4.65; N, 21.53.Found: C, 36.90; H, 4.79; N, 21.43.

Example 23 1-(2',3',5'-Tri-O-benzoyl-β-L-ribofuranosyl)-6-methyluracil(40)

A mixture of 6-methyluracil (2.52 g, 20.0 mmol), hexamethyldisilazine(50 mL) and ammonium sulfate (100 mg ) were refluxed at 135° C. for 6 h.The solvent was removed in vacuo and the residue that obtained wasco-evaporated twice with dry toluene (2×50 mL) to remove last traces ofhexamethyldisilazine. The solid thus obtained was dried under vacuum for6 h. A solution of the 2,4-bis(trimethylsilyloxy)-6-methylpyrimidine(20.0 mmol) in dry acetonitrile (100 mL) was added1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (10.12 g, 20 mmol) andtrimethylsilyltriflate (5.78 g, 26.0 mmol). The reaction mixture wasstirred under argon at room temperature for 16 h. The reaction mixturewas concentrated in vacuo and the residue was dissolved indichloromethane (200 mL). The organic layer was washed with sat. sodiumbicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate andconcentrated to yield a white foam. Further separation of the crudeproduct by silica gel flash column chromatography using the CH₂ Cl₂→EtOAc as the eluent gave two products. Yield of the 2^(nd) fraction4.50 g (42%). ¹ H NMR (CDCl₃) δ 2.28 (s, 3H, CH₃), 4.65-4.81 (m, 3H,C_(4') H and C_(5') H), 5.60 (m, 1H, C_(3') H), 5.72 (s, 1H), 6.11 (m,1H), 7.24-8.06 (m, 16H, PhH) and 9.40 (br s, 1H, NH). The first fraction(4.20 g) did not correspond to the desired compound according to ¹ HNMR.

Example 24 1-β-L-Ribofuranosyl-6-methyluracil (41)

A solution of 40 (4.50 g, 7.86 mmol) was dissolved in sat. methanolicammonia (60 mL). The reaction mixture was heated at 100° C. for 17 h ina steel bomb. The reaction vessel was cooled to room temperature andconcentrated to yield an oil. The reside was further purified by silicagel flash column chromatography using dichloromethane and methanol (9:1)as the eluent. Pure fractions were collected and evaporated to give awhite solid. This was further recyrstallized from 2-propanol to afford1.98 g (94%) of pure 41: mp 175-177° C.; ¹ H NMR (Me₂ SO-d₆) δ 2.24 (s,3H, CH₃), 3.42-3.57 (m, 2H, C_(5') H), 3.68 (m, 1H, C_(4') H), 4.0 (m,1H, C_(3') H), 4.53 (m, 1H, C_(2') H), 4.68, 4.94, 5.22 (m, 3H, 3 OH, D₂O exchangeable), 5.43 (d, 1H, C_(1') H, J_(1'), 2' =3.85 Hz), 5.56 (s,1H, C₅ H) and 11.25 (s, 1H, NH). Anal. Calc. for C₁₀ H₁₄ N₂ O₆ (258.23):C, 46.51; H, 5.46; N, 10.85. Found: C, 46.66; H, 5.26; N, 10.66.

Example 25 1-(2',3',5'-Tri-O-benzoyl-β-L-ribofuranosyl)-5-azacytidine(42)

5-Azacytosine (1.12 g, 10.0 mmol) was suspended in a mixture ofhexamethyldisilazine (50 mL) and of ammonium sulfate(l 00 mg). Thereaction mixture was refluxed at 135° C. for 6 h. Later, the solventswere removed in vacuo and the residue thus obtained was co-evaporatedtwice from dry toluene (2×50 mL) to remove last traces ofhexamethyldisilazine. The solid thus obtained was dried under vacuo for6 h. To a solution of 2,4-N, bis(trimethylsilyl)-5-azacytidine (10.0mmol) in dry 1,2-dichlorethane (150 mL) was added1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose (5.06 g, 10 mmol) andtin tetrachloride (1.68 mL, 14.16 mmol) at 10° C. The reaction mixturewas stirred under the atmosphere of argon at 10° C. for 2 h. Thereaction was checked by TLC using hexane and ethyl acetate (7:3). TLCindicated that no starting material remained. The reaction mixture wasdiluted with dichloromethane (250 mL). The organic layer is washed withsat. sodium bicarbonate (200 mL) and brine (100 mL), dried over sodiumsulfate and concentrated to a residue. The residue was dissolved intoluene and filtered through celite to remove unreacted 5-azacytosine.The filtrate was evaporated to dryness and the residue (5.20 g) wasdissolved in ethanol and filtered again through celite. The titledcompound was crystallized from the filtrate as needles 4.45 g (81%): mp186-187° C.; ¹ H NMR (CDCl₃) δ 4.62-4.66 (m, 3H, C_(4') H and C_(5') H),6.01 (m, 3H, C_(1') H, C_(2') H and C_(3') H), 7.26-8.06 (m, 17H, NH₂and PhH) and 8.48 (s, 1H, C₆ H).

Example 26 4-Amino-1-β-L-ribofuranosyltriazin-2(1H)-one (5-Azacytidine,43)

Compound 42 (4.0 g, 7.19 mmol) was dissolved in absolute methanol (60mL), heated to the boiling and treated with 0.5 M sodium methoxide (20mL, 10.0 mmol). The starting material rapidly dissolved and the solutionimmediately deposited the product. The mixture was kept for 4 h at roomtemperature and overnight in a refrigerator. The crystals are collected,washed with ice-cold methanol (10 mL) and dried under reduced pressureat room temperature. Yield 1.50 g (86%). Analytical sample was obtainedby re-crystallization from water-acetone (1:1): mp 220-222° C.; ¹ H NMR(D₂ O) δ 3.78-3.97 (m, 2H, C_(5') H), 4.13 (m, 1H, C_(4') H), 4.20 (m,1H, C_(3') H), 4.33 (m, 1H, C_(2') H), 6.31 (d, 1H, C_(1') H, J_(1'),2'=2.5 Hz) and 8.24 (s, 1H, C₆ H). Anal. Calc. for C₈ H₁₂ N₄ O₅ (244.20):C, 39.35; H, 4.95; N, 22.94. Found: C, 34.09; H, 4.28; N, 22.98.

Example 27 1-(2',3',5'-Tri-O-benzoyl-β-L-ribofuranosyl)-6-azauridine(44)

6-Azauracil (1.36 g, 12.0 mmol), was suspended in a mixture ofhexamethyldisilazine (50 mL) and ammonium sulfate (50 mg). The reactionmixture was refluxed at 135° C. for 6 h. Later, the solvents wereremoved in vacuo and the residue that obtained was co-evaporated twicefrom dry toluene (2×50 mL) to remove last traces ofhexamethyldisilazine. The solid was dried in vacuo for 6 h and used inthe next step of synthesis without further characterization. To asolution of the 2,4-bis(trimethylsilyl)-6-azauridine (12.0 mmol) in dry1,2-dichlorethane (60 mL) was added1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10 mmol) and tintetrachloride (1.68 mL, 14.16 mmol) at 10° C. The reaction mixture wasstirred under the atmosphere of argon at room temperature for 6 h. Thereaction was checked by TLC using hexane and ethyl acetate (7:3). TLCindicated no starting material remained. The reaction mixture wasdiluted with dichloromethane (250 mL). The organic layer is washed withcold sat. sodium bicarbonate (150 mL) and brine (100 mL), dried oversodium sulfate and concentrated to a white foam. The residue wasdissolved in dichloromethane (100 mL) and filtered through celite toremove unreacted 6-azauracil. The filtrate was evaporated to a residue(4.50 g), dissolved in minimum amount of ethanol and filtered againthrough celite. The title compound was crystallized from the filtrate asneedles to give 4.50 g (79%) of pure 44: mp 193-195° C.; ¹ H NMR (Me₂SO-d₆) δ 4.47-4.67 (m, 3H, C₅ NH), 4.71 (m, 1H, C_(4') H), 5.85 (m, 1H,C_(3') H), 5.93 (m, 1H, C_(2') H), 6.38 (d, 1H, J_(1'),2' =2.56 Hz,C_(1') H), 7.26-8.06 (m, 16H, C₅ H and PhH) and 12.32 (s, 1H, NH).

Example 28 1-β-L-Ribofuranosyl-6-azauracil (6-Azauridine 45)

Compound 44 (4.5 g, 7.95 mmol) was dissolved in absolute methanolicammonia (60 mL) and placed in a steel bomb. The was heated at 100° C.for 16 h. Later, the reaction vessel was cooled to room temperature andthe solvent was removed under vacuum. The residue that obtained wastriturated with hot toluene (2×50 mL). The residue was dissolved in 95%ethanol and left at room temperature. The white solid crystals that wereobtained was collected by filtration and dried in vacuo. Yield 1.75 g(89%): mp 151-153° C.; ¹ H NMR (Me₂ SO-d₆) δ 3.30-3.47 (m, 2H, C_(5')H), 3.73 (m, 1H, C_(4') H), 3.92 (m, 1H, C_(3') H), 4.17 (m, 1H, C_(2')H), 4.62, 4.98, 5.22 (3br s, 3H, 3 OH, D₂ O exchangeable), 5.82 (d, 1H,C_(3') H, J_(1'),2' =3.85 Hz), 7.48 (s, 1H, C₅ H) and 11.20 (brs, 1H,NH). Anal. Calc. for C₈ H₁₁ N₃ O₆ (245.19): C, 39.19; H, 4.52; N, 17.14.Found: C, 38.81; H, 4.58; N, 17.04.

Example 29 Diethyl imidazole-4,5-dicarboxylate (46)

Imidazole-4,5-dicarboxylic acid (7.55 g, 50.0 mmol) is dissolved inabsolute ethyl alcohol (120 mL). The solution was cooled in an ice bathto 0° C. and bubbled dry HCl gas for 1 h. Later, the reaction mixturewas refluxed at 80° C. for 7 h during which time all the startingmaterial was consumed. The solvent was removed and the residue thatobtained was dissolved in dichloromethane (200 mL) and the organic layerwas neutralized with triethylamine. The organic layer was washed withcold water (100 mL) and brine (50 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo to give 5.50 g (52%) of white solid:mp 175-177° C.; ¹ H NMR (CDCl₃) δ 1.40 (t, 3H), 4.41 (m, 2H), 7.84 (1H,C₂ H) and 11.55 (br s, 1H, NH).

Example 30 Diethyl1-(2',3',5'-tri-O-benzoyl-β-L-ribofuranosyl)imidazole-4,5-dicarboxylate(47)

A mixture of diethyl imidazole-4,5-dicarboxylate (2.65 g, 12.50 mmol)and ammonium sulfate (50 mg) was heated at reflux at 135° C. for 6 hwith hexamethyldisilazine (50 mL). The reaction mixture was evaporatedto dryness and the residue was co-evaporated twice with dry toluene(2×50 mL) to remove last traces of hexamethyldisilazine. The solid thatobtained was dried in vacuo for 6 h and used for the next step withoutfurther characterization. To a solution of the above residue (12.5 mmol)in 1,2-dichlorethane (60 mL) was added1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10 mmol) and tintetrachloride (1.68 mL, 14.16 mmol) at 10° C. The reaction mixture wasstirred under the atmosphere of argon at room temperature for 6 h. Thereaction was checked by TLC using hexane and ethyl acetate (7:3). TLCindicated no starting material remained. The reaction mixture wasdiluted with dichloromethane (200 mL). The organic layer was washed withcold sat. sodium bicarbonate (200 mL) and brine (100 mL), dried oversodium sulfate and concentrated to yield a white foam. The residue wasdissolved in dichloromethane (100 mL) and filtered through celite toremove tin salts. After evaporation in vacuo the residue (4.70 g) wasdissolved in ethanol and filtered again through celite. The titledcompound 47 was crystallized from the filtrate as needles. Yield 4.70 g(72%): mp 134-136° C.; ¹ H NMR (CDCl₃) δ 1.28 (t, 3H, CH₃), 1.37 (t, 3H,CH₃), 4.28-4.40 (m, 4H, 2 CH₂), 4.65-4.88 (m, 3H, C_(4') H and C_(5')H), 5.85 (m, 2H, C_(2') H and C₃,h), 6.68 (d, 1H, C H, J_(1'),2' =3.90Hz) and 7.26-8.08 (m, 16H, C₂ H and PhH).

Example 31 1-β-L-Ribofuranosylimidazole-4,5-dicarboxamide (48)

Compound 47 (4.0 g, 6.09 mmol) was dissolved in of absolute methanolicammonia (60 mL) and heated at 100° C. for 16 h in a steel bomb. Later,the reaction mixture was cooled to room temperature. The productcrystallized out from methanol. The precipitated product was removed byfiltration and the filtrate was concentrated further to yield the secondcrop of the product. The combined product was recyrstallized once againfrom methanol to furnish 1.68 g (100%) of white solid: mp 224-226° C.; ¹H NMR (Me₂ SO-d₆) δ 3.53-3.75 (m, 2H, C_(5') H), 3.84 (m, 1H, C_(4') H,3.96 (m, 2H, C_(2') H and C_(3') H), 4.97,5.16, 5.36 (3br s, 3H, 3 OH,D₂ O exchangeable ), 6.49 (d, 1H, C_(1') H, J_(1'),2' =2.1 Hz), 7.60 (s,1H, CONH₂), 7.88 (s, 1H, CONH₂), 7.99 (s, 1H, CONH₂), 8.48 (s, 1H, C₂ H)and 10.59 (s, 1H, CONH₂). Anal. Calc. for C₁₀ H₁₄ N₄ O₆ (286.24): C,41.96; H, 4.93; N, 19.57. Found: C, 41.89; H, 5.05; N, 19.41.

Example 32 Ethyl1-(2',3',5'-tri-O-benzoyl-β-L-ribofuranosyl)-3-hydroxy-1,2-pyrazole-4-carboxylate(49)

A mixture of ethyl 3-Hydroxy-1,2-pyrazole-4-carboxylate (1.95 g, 12.50mmol) and ammonium sulfate (50 mg) in hexamethyldisilazine (50 mL) washeated at reflux for 6 h. The reaction mixture was evaporated to drynessand the residue that obtained was co-evaporated twice with dry toluene(2×50 mL) to remove last traces of hexamethyldisilazine. The solid thatobtained was dried in vacuo for 6 h and used as such for furtherreaction. To a solution of the above trimethylsilyl derivative (12.5mmol) in dry 1,2-dichlorethane (60 mL) was added 1-O-acetyl2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10 mmol) and tintetrachloride (1.68 mL, 14.16 mmol) at 10° C. The reaction mixture wasstirred under the atmosphere of argon at room temperature for 6 h. Thereaction mixture was diluted with dichloromethane (200 mL). The organiclayer was washed with sat. sodium bicarbonate (200 mL), water (100 mL)and brine (100 mL), dried over sodium sulfate and concentrated to afoam. The residue was dissolved in dichloromethane (70 mL) and filteredthrough celite to remove tin salts. The crude product was purified bysilica gel flash column chromatography using CH₂ Cl₂ →EtOAc as theeluent. Pure fractions were pooled and evaporated to give 3.50 g (57%)of a white foam: ¹ H NMR (CDCl₃) δ 1.36 (t, 3H, CH₃), 4.30 (m, 2H, CH₂),4.52-4.82 (m, 3H, C_(4') H and C_(5') H), 6.08-6.32 (m, 3H, C_(1') H,C_(2') H and C_(3') H) and 7.26-8.08 (m, 16H, C₅ H and PhH).

Example 33 1-β-L-Ribofuranosyl-3-hydroxy-1,2-pyrazole-4-carboxamide (50)

A solution of 49 (3.50 g, 5.71 mmol) in sat. methanolic ammonia (60 mL)was heated at 100° C. for 16 h in a steel bomb. The reaction mixture wascooled to room temperature and concentrated. The residue was trituratedwith toluene (2×50 mL) to remove benzamide. The residue was dissolved inminimum quantity of absolute ethanol and left at room temperatureovernight. The crystals that obtained was removed by filtration and thefiltrate was concentrated further to yield second crop of the product.The combined product recyrstallized once again from ethanol to the solidwhich was collected by filtration and dried in vacuo to yield 1.0 g(68%): mp 178-180° C.; ¹ H NMR (Me₂ SO-d₆) δ 3.37-3.52 (m, 2H, C_(5')H), 3.78 (m, 1H, C_(4') H), 3.98 (m, 1H, C_(3') H), 4.19 (m, 1H, C_(2')H), 4.81, 5.05, 5.34 (3br s, 3H, 3 OH, D₂ O exchangeable), 5.38 (d, 1H,C_(1') H, J_(1'),2' =4.2 Hz), 6.98 (bs, 1H, CONH₂), 7.16 (bs, 1H,CONH₂), 8.08 (s, 1H, C₅ H) and 10.98 (bs, 1H, C₃ OH). Anal. Calc. for C₉H₁₃ N₃ O₆ (259.22): C, 41.70; H, 5.05; N, 16.21. Found: C, 41.52; H,5.23; N, 16.40.

Example 34 1-Azido-2,3-isopropylidine-b-L-ribofuranose (51)

To a solution 2,3,5-tri-O-benzoyl-1-azido-b-L-ribofuranose (9.0 g, 18.48mmol) in absolute methanol (60 mL) was added 0.5 M solution of sodiummethoxide (10.0 mL, 5.0 mmol). The reaction mixture was stirred at roomtemperature overnight. TLC of the reaction (hexane/ethyl acetate; 7:3)indicated complete conversion of the starting material to a more polarcompound. The reaction mixture was neutralized with dry Dowex 50 H⁺resin and the resin was removed by filtration. The filtrate wasevaporated to dryness and dissolved in water (50 mL). The aqueous layerwas extracted with dichloromethane (2×100 mL) to remove methyl benzoateand then the aqueous layer was concentrated in vacuo. The residue wasfurther dried over phosphorous pentoxide and used as such for the nextstep of the synthesis without further characterization.

The above crude product (3.0 g, 17.14 mmol) was suspended in dry acetone(200 mL) and treated with 1,1-dimethoxypropane (50 mL) and vacuum driedDowex 50 H⁺ (5.0 g) resin. The reaction mixture was stirred at roomtemperature for 2 h and filtered and the resin was washed with dryacetone (100 mL). The filtrate was evaporated to dryness. The residuewas purified by flash chromatography over silica gel using CH₂ Cl₂→EtOAc as the eluent. The pure fractions were pooled and concentrated togive 3.60 g (97%)of product as oil: ¹ H NMR (CDCl₃) d 1.44 and 1.27 (2s,6H, isopropylidene CH₃), 2.70 (br s, 1H, C_(5') OH, exchangeable), 3.66(m, 2H, C_(5') H), 4.34 (m, 1H, C_(4') H), 4.46 (d, 1H, C_(3') H), 4.72(d, 1H, C_(2') H) and 5.50 (s, 1H, C_(1') H).

Example 351-Azido-2,3-O-isopropylidine-5-O-tert-butyldimethylsilyl-b-L-nibofuranose(52)

To a solution of 1-azido-2,3-O-isopropylidine-b-L-ribofuranose (4.20 g,20 mmol) in dry DMF (25 mL) was added imidazole (2.38 g, 35.0 mmol) and

tert-butyldimethylsilyl chloride (4.50 g, 30.0 mmol). The reactionmixture was stirred at room temperature under argon atmosphereovernight. TLC of the reaction mixture after 16 h indicated completeconversion of the starting material to the product. The solvent wasremoved in vacuo and the residue dissolved in dichloromethane (200 mL).The organic layer is washed with water (100 mL), satd. sodiumbicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate andconcentrated to an oily product. Further purification by silica gelflash column chromatography using hexane/ethyl acetate (9:1) gave 6.22 g(94%) of the titled compound as oil: ¹ H NMR (CDCl₃) d 0.07 (s, 6H), 0.9(s, 9H), 1.27 and 1.47 (2s, 6H, isopropylidene CH₃), 3.66 (m, 2H, C_(5')H), 4.34 (m, 1H, C_(4') H), 4.46 (d, 1H, C_(3') H), 4.72 (d, 1H, C_(2')H) and 5.50 (s, 1H, C_(1') H).

Example 361-Amino-2,3-O-isopropylidine-5-O-tert-butyldimethylsilyl-β-L-ribofuranose(53)

To a mixture of 1-azido-2,3-O-isopropylidine-β-L-ribofuranose (6.0 g, 18mmol) and Pd/C (0.25 g) in MeOH (50 mL) was hydrogenated at 50 psi on aparr hydrogenator overnight. The reaction mixture was filtered and thecatalyst washed with methanol(20 mL). The combined filtrate wasevaporated to dryness and dried over P2O5 at vacuo overnight and used assuch for the next reaction without characterization. Yield 5.0 g (90%).

Example 37 Ethyl5-amino-(2',3'-O-isopropylidine-5'-O-tert-butyldimethylsilyl-β-L-ribofuranosyl)imidazole-4-carbozylate(54)

To a stirred solution of 53 (5.0 g, 16.44 mmol) in dry CH₂ Cl₂ (60 mL)was added a solution of ethylN-cyano-N-(ethoxycarbonylmethyl)formimidate (4.0 g, 22. 18 mmol;Robinson, D. H., et al, J. Chem Soc., Perkin 1, 1715-1717, 1972) during15 min period. The reaction mixture was stirred at room temperatureovernight under argon atmosphere. The reaction was diluted with CH₂ Cl₂(100 mL) and the organic layer was washed with sat. NaHCO3 (100 mL),water (50 mL) and brine (50 mL). The organic extract was dried andconcentrated to give a crude product. The crude product was purified byflash chromatography over silica gel using CH₂ Cl₂ →EtOAc as the eluent.The pure fractions were pooled and evaporated to five 5.50 g (76%) aswhite foam: ¹ H NMR (CDCl₃) δ 0.28 (m, 6H), 1.1 (m, 9H), 1.55 (m, 9H),4.00 (m, 2H, C₅ H), 4.53 (m, 3H), 5.0 (m, 1H), 5.78 (m, 1H), 6.06 (d,1H, C_(1') H) and 7.44 (s, 1H, C₂ H).

Example 385-amino-(2',3'-O-isopropylidine-5'-O-tert-butyldimethylsilyl-β-L-ribofuranosyl)imidazole-4-carboxamide(55)

A solution of 54 (5.0 g, 11.33 mmol) in methanolic ammonia (60 mL) washeated at 100° C. in a steel bomb for 12 h. The steel bomb was cooled,opened carefully and concentrated. The crude product was purified byflash chromatography over silica gel using CH₂ Cl₂ →EtOAc as the eluent.The pure fractions were pooled and evaporated to give 4.0 g (88%) aswhite foam.

Example 395-Amino-(2',3'-O-isopropylidine-β-L-ribofuranosyl)imidazole-4-carboxamide(56)

To a stirred solution of 55 (4.0 g, 9.97 mmol) in dichloromethane (50mL) was added Et₃ N.3HF (50 mmol) at room temperature. The reactionmixture was stirred overnight and evaporated to dryness. The residue waspurified by flash chromatography over silica gel using CH₂ Cl₂ →EtOAc asthe eluent. The pure fractions were pooled and evaporated to give 2.10 g(71%) as white foam.

Example 40 5-Amino-1-β-L-ribofuranosylimidazole-4-carboxamide (5)

To a stirred solution of 56 (2.0 g, 6.71 mmol) in dichloromethane (20mL) was added 90% CF₃ COOH (20 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h and evaporated to dryness. The residue wascoevaporated with dry methanol (20 mL). This process was repeated threetimes to remove last traces of TFA. The residue was treated with NH₄ OH(10 mL) and evaporated to dryness. The residue was evaporated with dryethanol (3×20 mL). The residue was crystallized from ethanol to give 1.5g (87%) of pure product.

Example 41 Methyl 1-β-L-(2',3',5'-Tri-O-benzoyl)ribofuranosyl-2-oxo-Δ⁴-imidazoline-4-carboxylate (59)

A mixture of methyl 2-oxo-Δ⁴ -imidazoline-4carboxylate 58 (542 mg, 3.82mmol), hexamethyldisilazane (HMDS, 28 mL) and (NH₄)₂ SO₄ (75 mg, 0.56mmol) were heated at reflux. A clear solution formed in 40 min and thereaction was maintained at reflux for another 3.5 h. The excess HMDS wasevaporated and the product, a brown oil, further dried under vacuum for1 h.

A solution of 1-O-acetyl-2,3,5-O-tri-benzoyl-L-ribofuranose (1.93 g,3.82 mmol) in anhydrous dichloroethane (28 mL) was added to the abovedried silyl base at room temperature followed by dropwise addition ofSnCl₄ (1.39 g, 0.63 mL, 5.35 mmol). After addition, the reaction mixturewas allowed to stay at room temperature overnight (˜17 h). The reactionmixture was filtered through a silica gel pad flushed with EtOAc. TheEtOAc solution was washed with sat. NaHCO₃, filtered, washed with brinetwice. The organic phase was separated dried over Na₂ SO₄, concentrated,and purified by flash chromatography over silica gel using (86% CH₂ Cl₂,14% EtOAc) to give 797 mg (36%) of the product as an off-white solid: ¹H NMR (Me₂ SO-d₆) δ 3.70 (s, 3H), 4.60 (dd, 1H, J_(1'),2' =12.7, 6.6Hz,), 4.70 (m, 2H), 5.93 (dd, 1H), 5.98 (d, 1H), 6.05 (dd, 1H), 7.46 (m,6H), 7.63 (m, 3H), 7.71 (s, 1H), 7.91 (m, 6H) and 11.15 (s, 1H).

Example 42 1-β-L-Ribofuranosyl-2-oxo-Δ⁴ -imidazoline-4-carboxamide (60)

Compound 59 (1.26 g, 2.15 mmol) was dissolved in methanolic ammonia (45mL, pre-saturated with NH₃ at 0° C.). The solution was sealed in a steelbomb and heated at 95° C. for 15 h. The reaction mixture was cooled toroom temperature, the solvent was evaporated, and the residue washedwith CHCl₃ three time to remove the benzamide generated from thereaction. The residue was then added with MeOH (15 mL) and heated atreflux. CHCl₃ was added to the clear solution at reflux slowly untiltrace of precipitate generated. The hot mixture was filtered quickly bysuction and the filtrate solution was evaporated to dryness to give alight brown oil. The oil was soaked with anhydrous CH₃ CN afforded theproduct as a light brown solid: Yield 322 mg (58%); mp 174-178° C. ¹ HNMR (Me₂ SO-d₆) δ 3.48 (m, 2H), 3.77 (m, 1H), 3.94 (m, 1H), 4.05 (m,1H), 4.90 (m, 1H), 5.08 (d, 1H), 5.30 (d, 1H), 5.36 (d, 1H), 7.30 (s,1H), 7.31 (br s, 2H) and 10.47 (br s, 1H).

Example 43 2,3,5-Tri-O-benzoyl-β-L-ribofuranosyl-1-carbonitrile (61)

To a stirred mixture of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose(dried at 60° C., 1 mm, 12 h; 12.6 g, 24.9 mmol) in dry dichloromethane(dried over magnesium sulfate and stored over molecular sieves, 125 mL)at 0-2° C. was added trimethylsilyl cyanide (dried over molecularsieves, 24 h; 4.70 mL, 37.50 mmol) under argon atmosphere. To thisreaction mixture was then added stannic chloride (1.0 mL, 8.67 mmol)slowly while maintaining a reaction temperature at 0-2° C. The resultingmixture was stirred and maintained at -5 to 0° C. for an additional 1.5h. After 2 h, the reaction mixture was added slowly into a vigorousstirring cold (5° C.) 10% sodium hydroxide solution (1.5 L) during 30min period and the mixture was maintained at 5-8° C. throughout theaddition. The layers were separated and the organic layer was washedwith water (3×500 mL) until neutral and then dried over anhydrousmagnesium sulfate. The organic extract was filtered and the drying agentwas washed with dichloromethane (3×50 mL). The filtrate and washingswere combined and the solution was concentrated (<30° C., 20 mm) to alow volume and the remaining solution was filtered through a bed ofcelite. Further purification was achieved by silica gel flash columnusing dichloromethane as eluent. The dichloromethane solutions werecombined and evaporated (<30° C., 20 mm) to give a white foam. The crudeproduct was purified by flash chromatography over silica gel usingdichloromethane as the eluent. The pure fractions were combined andevaporated to give a syrup. The syrup was mixed with dry ethanol (100mL) and the mixture was heated (approx. 60° C.) to obtain a homogeneoussolution. Cooling of this solution to room temperature gave whitecrystalline product. The crystalline solid was filtered and washed withcold ethanol and dried over P₂ O₅ to give 7.47 g (63%) of 61: mp 55-57°C.; ¹ H NMR (CDCl₃) δ 4.61 (m, 1H, C_(4') H), 4.78 (m, 2H, C_(5') H),5.00 (d, 1H, C_(1') H), 5.88 (t, 1H, C_(3') H), 6.05 (m, 1H, C₂ H),7.45-8.07 (m, 15H, PhH).

Example 44 2,3,5-Tri-O-benzoyl-β-L (+)-ribofuranosyl allonthioamide (62)

To a suspension of L-cyanosugar 61 (6.10 g, 12.95 mmol) in dry ethanol(105 mL) was passed H₂ S for 10 min. To this solution was then addedN,N-dimethylaminopyridine (DMAP, 158 mg, 1.3 mmol). The reaction waskept at 15-20° C. and sat. with H₂ S during 21/2 h period. (Note: Thestarting material which was a suspension was dissolved during the courseof reaction). After 21/2 h, the H₂ S bubbling was stopped, the reactionmixture was stoppered and allowed to stir at room temperature overnight.The reaction was checked by TLC next day morning (Hexane/EtOAc; 7:3).TLC indicated complete conversion of the starting material to theallothioamide . The reaction mixture was cooled on an ice bath and argonwas bubbled through this for 1 h to remove the excess H₂ S. Later thereaction mixture was concentrated on a rotavapor to yield 6.20 g (95%)of a foamy material: ¹ H NMR (CDCl₃) δ 4.78 (m, 3H, C_(4') H and C_(5')H), 5.12 (d, 1H, C_(1') H), 5.72 (t, 1H, C_(3') H), 5.98 (m, 1H, C_(2')H), 7.45-8.12 (m, 15H, PhH) and 8.50 (br s, 2H, NH₂).

Example 45 Ethyl 2-(2', 3',5'-Tri-O-benzoyl-β-L(+)-ribofuranosyl)thiazole-4-carboxylate (63)

To a stirred suspension of allothioamide 62 (5.05 g, 10 mmol) in dry1,2-dimethoxyethane (DME, 100 mL) at 0° C. was added of anhydrous NaHCO₃(8.4 g, 100 mmol). To this suspension under argon was added ofethylbromopyruvate (3.75 mL, 30 mmol) dropwise during 10 min period. Thereaction mixture was stirred at 0° C. for 5 h under argon. The reactionwas analyzed by TLC (Hex/EtOAc; 7:3). TLC indicated traces of startingmaterial. The reaction was left additional 1 h at 0-5° C., by which timemost of the starting material was converted into the product. Then, thereaction mixture was cooled to -15° C. in dry ice/acetone bath. To thereaction mixture was then added dropwise through a dropping funnel asolution of 2,6-lutidine (7.0 mL , 60 mmol) and trifluoroaceticanhydride (4.16 mL, 30 mmol) in dry DME (20 mL) during 15 min period.The reaction mixture temperature was maintained at -15° C. for 2 h underargon. Then, the reaction mixture was filtered and concentrated. Theresidue that obtained was dissolved in CH₂ Cl₂ (200 mL) and the organiclayer was washed with 5% NaHCO₃ (100 mL), 1N HCl (100 mL), 5% NaHCO₃(100 mL), water (100 mL) and brine 100 mL), dried and concentrated to adark red color oil. The crude product was purified by silica gel flashcolumn chromatography using hexane/EtOAc (7:3) as the eluent gave 5.96 g(99%) of pure product: ¹ H NMR (CDCl₃) δ 1.30 (t, 3H, CH₂ CH₃), 4.30 (t,2H, CH₂ CH₃), 4.55-4.78 (m, 3H, C_(4') H and C_(5') H), 5.72 (d, 1H),5.82 (m, 2H), 7.25-8.04 (m, 15H, PhH) and 8.06 (s, 1H, C₅ H).

Example 46 β-L (+)-Ribofuranosylthiazole-4-carboxylic acid ethyl ester(64)

Compound 63 (6.0 g, 10 mmol) was dissolved in dry ethanol (60 mL) (Note:the compound was dissolved by warming with hot air gun). To thissolution under argon was added NaOEt (200 mg, 3.0 mmol) powder. Thereaction mixture was stirred under argon overnight. The reaction waschecked by TLC using hexane /EtOAc 7:3 and EtOAc/MeOH 9:1). TLC hasindicated complete conversion of the starting material to a more polarproduct. Then, the reaction was neutralized with dry Dowex 5x-8 H⁺resin. The resin was removed by filtration and the filtrate wasconcentrated under vacuum on a rotavapor. The brown colored residue wasthen purified by silica gel flash column chromatography usingEtOAc→MeOH. The pure fractions were pooled and concentrated to furnish2.31 g (77%) of pure product. ¹ H NMR (CDCl₃) δ 1.30 (t, 3H, CH₂ CH₃),3.56 (m, 2H, C_(5') H), 3.86 (m, 2H), 4.0 (m, 1H), 4.26 (t, 2H, CH₂CH₃), 4.82-5.04 (3m, 3H, 3 OH), 5.42 (d, 1H, C_(1') H) and 8.46 (s, 1H,C₅ H).

Example 47 β-L(+)-Ribofuranosylthiazole-4-carboxamide (65)

A solution of 64 (1.0 g, 3.32 mmol) in methanolic ammonia (50 mL) wasstirred at room temperature in a steel bomb. After 17 h, the bomb wascooled, opened carefully and the solution was evaporated to a residue.The residue was chromatographed on a silica gel flash columnchromatography using ethyl acetate and methanol (9:1) as the eluent. Theproduct is crystallized from absolute ethanol. Yield 580 mg (67%): mp146-148° C.; ¹ H NMR (Me₂ SO-d₆) δ 3.48 (m, 2H, C_(5') H), 3.85 (m, 2H),4.03 (m, 1H), 4.80 (t, 1H, C_(5'H)), 4.88 (d, 1H, C_(3') OH), 5.32 (d,1H, C_(2') OH), 5.02 (d, 1H, C_(1') H,J_(1'),2' =5.1 Hz), 7.52 (bs, 1H,CONH₂), 7.64 (bs, 1H, CONH₂) and 8.16 (s, 1H, C₅ H). Anal Calc. for C₉H₁₂ N₂ SO₅ (260.2): C, 41.53; H, 4.65; N, 10.76; S, 12.32. Found: C,41.73; H, 4.60; N, 10.55; S, 12.25.

Example 48 β-L-Ribofuranosyl-1-carboximidic Acid Methyl Ester (66)

To a stirred suspension of 2,3,5-tri-O-benzoyl-β-L-ribofuranosyl cyanide(14.13 g, 30.0 mmol) in dry methanol (60 mL) was added sodium methoxide(0.358 g, 6.64 mmol, 0.5 M solution, Fluka) under argon atmosphere. Thesolution, which became homogeneous in 5 min, was stirred for 2.5 h atroom temperature. The reaction mixture was neutralized with Dowex 50W-X8H⁺ resin (dried at 100° C. under 0.05 mm Hg 16 h; 3.0 g, 5.1 molarequiv/g). The resin was filtered and the solvent was removed below 40°C. on a rotavapor. The residue that obtained was washed with methanol.The methanol washings were concentrated to obtain second and third cropsof 66. The three crops were combined and recyrstallized from drymethanol to provide 4.35 g (66%): mp 140-142° C.; ¹ H NMR (CDCl₃) δ 3.46(s, 3H, OCH₃), 3.50-3.80 (m, 5H), 3.98 (d, 1H), 4.98 (br s, 3H) and 8.27(s, 1H, NH).

Example 492-[(Aminocarbonyl)carbonyl]-1-(β-L-ribofuranosyliminomethyl)hydrazine(67)

Methyl imidate 66 (4.83 g, 25.26 mmol) and oxamidohydrazide (2.68 g,26.00 mmol) were dissolved in dry dimethyl sulfoxide (100 mL). After thereaction solution was stirred for 20 h at room temperature, the solventwas distilled off at 55° C. in vacuo. The residual solid was suspendedin methanol, and the soluble portion was collected by filtration (theinsoluble solid was found to be unreacted hydrazide) and concentrated toabout 25 mL. Addition of this solution drop-wise into acetonitrile (500mL) a white precipitate was obtained: yield 4.35 g (66%); ¹ H NMR (Me₂SO-d₆) δ 3.47-3.60 (m, 2H), 3.3.60-3.88 (m, 3H), 4.07 (d, 1H), 4.15 (d,1H), 4.85-5.2 (br s, 2H), 7.70, 8.09 (2 br s, 2H) and 10.05 (br s, 1H,C═NH).

Example 50 3-β-L-Ribofuranosyl-1,2,4-triazole-5-carboxamide(C-Ribavirin; 68)

Compound 67 (4.0 g, 15.2 mmol) was heated under vacuum (0.1 mm) at 135°C. for 15 min. After the flask was cooled, the glassy material wastreated with methanol and heated on a steam bath. During this process asolid started to precipitate. After about 2 h, the solid was isolated,and a second crop was obtained on concentration of the filtrate. Thetotal yield of the product was 2.65 g (71%): mp 193-195° C.; ¹ H NMR(Me₂ SO-d₆) δ 3.43 (m, 2H, C_(5') H), 3.75 (m, 1H, C₄ H), 3.88 (m, 1H,C_(3') H), 4.12 (m, 1H, C_(2') H), 4.57 (d, 1H, C_(1') H, J_(1'),2' =5.7Hz), 7.62 (bs, 1H, CONH₂), 7.86 (bs, 1H, CONH₂) and 10.0 (bs, 1H, NH).Anal. Calc. for C₈ H₁₂ N₄ O₅ (244.2): C, 39.35; H, 4.95; N, 22.94.Found: C, 39.38; H, 4.73; N, 22.43.

Example 51 5-O-Trityl-2,3-O-isopropylidene-b-L-ribofuranose (69)

To a solution of 2,3-O-isopropylidene-b-L-ribofuranose (10.5 g, 55.26mmol) in dry pyridine (100 mL) under argon was added catalytic amount ofDMAP (12.2 mg, 0.1 mmol). To this stirred solution was then added tritylchloride (15.56 g, 56.0 mmol). The reaction mixture was stirred underargon atmosphere overnight at room temperature. Pyridine was removedunder vacuum and the residue was dissolved in CH₂ Cl₂ (250 mL) and theorganic layer was washed with 10% NaHCO₃ solution (2×100 mL) and brine(100 mL). The organic layer was dried over Na₂ SO₄ and concentrated invacuo. The residue that obtained was purified by silica gel flash columnusing Hexane→EtOAc as the eluent. Pure fractions were pooled andconcentrated to give 15.74 g (69%) of product: ¹ H NMR (CDCl₃) δ 1.27and 1.41(2s, 6H, isopropylidene CH₃), 3.25-3.56 (m, 2H, C_(5') H), 3.86(m, 2H), 4.0 (m, 1H), 4.70 (m, 1H), 5.24 (d, 1H, J_(1'),2' =3.50 Hz,C_(1') H) and 7.17-7.35 (m, 15H, PhH).

Example 52 3-Ethoxycarbonyl-2-oxopropylidenetriphenyl-phosphorane (70)

A solution of {3-(ethoxycarbonyl)-2-oxopropyl}triphenyl phosphoniumchloride (21.34 g, 500 mmol) in water (450 mL) was added to a solutionof sodium carbonate (3.1 g, 25.0 mmol) in 10 min (Note: A whiteprecipitate was obtained immediately after the addition). This reactionmixture was stirred at room temperature overnight. The precipitate thatobtained was filtered off through a sintered funnel. The precipitate wasdissolved in dichloromethane (100 mL), dried over sodium sulfate andconcentrated to yield a white solid 18.13 g (93%). This material wasdried over phosphorus pentoxide overnight. ¹ H NMR (CDCl₃) δ 1.26 (t,3H), 3.34 (s, 2H), 3.76-3.84 (d, 1H) 4.19 (m, 2H) and 7.48-7.68 (m, 15H,PhH).

Example 53 Ethyl 4-(2',3'-O-Isopropylidene-5'-O-trityl-α- andβ-L-ribofuranosyl)-3-oxobutanoate (71)

A mixture 70 (10.9 g, 25.23 mmol) and3-ethoxycarbonyl-2-oxopropylidenetriphenyl-phosphorane (11.8 g, 30 mmol)in anhydrous acetonitrile (30 mL) was refluxed for 90 h. The solvent wasevaporated under reduced pressure and the residue was subjected to asilica gel flash column chromatography. Elution with hexane-ethylacetate (9:1) gave the product (β: α ca.2:1) as a foam (10.15 g, 74%).

Example 54 Ethyl 2-Diazo-4-(2',3'-O-isopropylidene-5'-O-trityl-α- and-β-L-ribofuranosyl)-3-oxobutanoate (72)

Triethylamine (1.83 g, 18.1 mmol) and toluene-p-sulphonyl azide (10 mL)were sequentially added to a solution of 71 (9.85 g, 18.08 mmol) inanhydrous acetonitrile (50 mL). The mixture was kept at room temperaturefor 30 min. The solvent was then evaporated under reduced pressure andthe residue was subjected to a silica gel flash column chromatography.Elution with hexane-ethyl acetate (9:1) gave 8.90 g (86%) of 72 (β: αca. 1:1) as a foam.

Example 55 Ethyl4-hydroxy-3-(2',3'-O-isopropylidene-5'-O-trityl-β-L-ribofuranosyl)pyrazole-5-carboxylate (73)

A solution of 72 (8.53 g, 14.92 mmol) in dry DME (60 mL) was addeddropwise to a stirred ice-cold suspension of sodium hydride (NaH) (60%dispersion; 1.80 g, 75.0 mmol) in dry DME (60 mL) under argon during 30min. The reaction temperature was raised gradually to 20° C., and themixture was stirred additional 3 h at room temperature. The reactionmixture was analyzed by TLC using hexane/EtOAc (3:1) ordichloromethane/EtOAc (9:1). TLC indicated completion of the reaction. Asolution of acetic acid (4.50 mL, 75.0 mmol) in DME (10 mL) was thenadded dropwise to the stirred ice-cold reaction mixture. The solvent wasevaporated under reduced pressure to give a residue to which water (50mL) and diethyl ether (100 mL) were added. The ethereal layer wasseparated, dried over anhydrous sodium sulfate and concentrated. Theresidue was subjected to silica gel flash column chromatography withhexane-ethyl acetate (3:1) as the eluent. Pure fractions were collectedand evaporated to give 73 as a mixture of β: α (6.40 g, 73%): ¹ H NMR(CDCl₃) δ 1.31 (t, 3H), 1.42-1.65 (m, 6H), 3.19-3.27 (m, 2H), 4.44-4.75(m, 3H), 4.75 (m, 1H), 5.19 (d, 1H), 6.99 (br s, OH, exchangeable),7.26-7.51 (m, 15H, PhH).

Example 564-Hydroxy-3-(2',3'-O-isopropylidene-5'-O-trityl-β-L-ribofuranosyl)pyrazole-5-carboxamide(74)

A solution of the ester 73 (6.30 g, 10.7 mmol) in dry methanolic ammonia(70 mL) was heated at 90-95° C. in a steel bomb for 12 h. The solventwas evaporated under reduced pressure and the residue was subjected tosilica gel flash column chromatography using hexane/ethyl acetate (3:2)as the eluent. The required fractions were pooled and evaporated to give4.54 g (78%) of the product as a glass containing a mixture of P: a. ¹ HNMR (CDCl₃) δ 1.40-1.62 (2s, 6H), 3.11-3.24 (m, 2H), 4.37 (m, 1H), 4.65(m, 1H), 5.11 (dd, 1H), 5.27 (d, 1H), 6.99 (br s, OH, exchangeable) and7.23-7.50 (m, 17H).

Example 57 3-β-L-Ribofruanosyl-4-hydroxypyrazole-5-carboxamide(L-Pyrazomycin; 75)

A solution of 74 (4.40 gm, 8.13 mmol) in 90% CF₃ CO₂ H (20 mL) wasstirred at room temperature for 45 min. Then the solvent was removed at5° C. under reduced pressure to give white solid (1.90 g, 90.48%). Theresidue that obtained was chromatographed on silica gel flash columnwith EtOAc-iPrOH--H₂ O (4:1:2) as the eluent. Fractions containing thepure compound b and a isomers were pooled separately and evaporated at<20° C. Recrystallization from water afforded 800 mg of pure β isomer:mp 111-113° C.; ¹ H NMR of β isomer (D₂ O) δ 3.73-3.78 (m, 2H), 4.0 (m,1H), 4.19 (m, 1H), 4.35 (m, 1H) and 4.90-4.93 (d, 1H, J_(1'),2' =7.42Hz). Anal. Calc. for C₉ H₁₃ N₃ O₆ (259.22): C, 41.70; H, 5.05; N, 16.21.Found: C, 41.88; H, 5.04; N, 16.58. Isolated yield of α: β mixture 1.90g, (90%).

100 mg of isomer was isolated as foam; ¹ H NMR of α isomer (D₂ O) δ3.65-3.85 (m, 2H), 4.06-4.11 (m, 1H), 4.32-4.41 (m, 2H), and 5.20 (d,1H, J_(1'),2' =3.30 Hz). Anal. Calc. for C₉ H₁₃ N₃ O₆ : C, 41.70; H,5.05; N, 16.21. Found: C, 41.91; H, 5.08; N, 16.02.

1.0 gm of inseparable mixture of L-pyrazomycin was also isolated.

The purity of the α: β isomers is also established by C18 reverse phaseHPLC using the gradient of acetonitrile 0-10% in water. The retentiontime of α isomer is Rt 5.716 and the β isomer 7.135. The purity of β andα mixture of L-pyrazomycin is found to be greater than 99.0% by HPLC.

Example 58 Preparation of 2,5-Anhydro-L-alloamidine hydrochloride (76)

Methyl 2,5-anhydro-L-allonimidate (3.82 g, 20.0 mmol) and ammoniumchloride (1.07 g, 20.0 mmol were dissolved in methanolic ammonia (60 mL,saturated at dry ice-acetone temperature for 1 h). Later this mixturewas allowed stir at room temperature in a thick walled steel bomb for 16h at room temperature. The steel bomb was cooled, opened carefully andthe solution was evaporated to dryness. The resulting solid was dried toyield 4.10 g of the titled compound in quantitative yield.

Example 59 2-(β-L-Ribofuranosyl)pyrimidine-6(1H)-oxo-4-carboxylic acid(77):

To a solution of 2,5-anhydro-L-alloamidine hydrochloride (4.0 g, 18.66mmol) in water (60 mL) was added sodium hydroxide (IN, 20 mL, 20.0 mmol)and ethyl sodium oxaloacetate (4.20 g, 20.0 mmol). The reaction mixturewas allowed to stir room temperature at 16 h at room temperature and wassubsequently neutralized to pH 2 with H+resin (Dowex 50W-X8). Thereaction mixture was filtered and concentrated to a minimum volume.Silica gel was added and evaporated to dryness. The resultant powder wasplaced on the top of a flash column and eluted with ethylacetate/acetone/methanol/water (3/1/1/1) mixture until the faster movingcompound was eluted. The column was then eluted with methanol and thefractions containing the compound were pooled and the methanol wasremoved to yield a tan color hygroscopic compound. Isolated yield 4.50 g(89%). This compound was used as such for the next step withoutcharacterization.

Example 60 Ethyl 2-(β-L-Ribofuranosyl)pyrimidine-6(1H)-oxo-4-carboxylate(78):

A thoroughly dried suspension of the acid 77 (4.50 g, 16.5 mmol) in ofdry ethanol (100 mL) was cooled in an ice bath and dry hydrogen chloridegas was bubbled for 5 min. To this reaction mixture was added triethylorthoformate (20 mL) and the mixture was allowed to stir for 24 h atroom temperature. The solvent was removed under vacuum and the resultantdark colored solid was purified further by silica gel flash columnchromatography using dichloromethane/methanol (9/1) mixture. Purefractions were pooled and concentrated to yield 4.55 g (92%) of a solidcompound. Since this compound was found to be impure, it is furtherconverted to the corresponding tetra acetate in 47% yield. The tetraacetate was purified by column chromatography.

Example 61 2-(β-L-Ribofuranosyl)pyrimidine-6(1H)-oxo-4-carboxamide (79)

A solution of the above tetra acetate ester (1.80 g, 4.22 mmol) in sat.methanolic ammonia (60 mL) was heated at 100° C. in a steel bomb for 17h. The reaction mixture was cooled and concentrated to yield a whitesolid. The solid was further triturated with ethyl acetate and filtered.The solid was recyrstallized from absolute ethanol to provide 0.83 g(82%) of pure product as white solid: mp 200-202° C.; ¹ H NMR (Me₂SO-d₆) δ 3.35-3.57 (m, 2H, C_(5') H), 3.84 (m, 1H, C_(4') H), 3.98 (m,1H, C_(3') H), 4.22 (m, 1H, C_(2') H), 4.75 (t, 1H, C_(5') OH, D₂ Oexchangeable), 4.80 (d, 1H, C_(1') H, J_(1'),2' =5.77 Hz), 4.89 (d, 1H,C_(3') OH, D₂ O exchangeable), 5.15 (d, 1H, C₂,OH, D₂ O exchangeable),7.85 (d, 1H), 7.98 (bs, 1H, CONH₂), 8.19 (bs, 1H, CONH₂) and 9.0 (d, 1H,NH). Anal. Calc. for C₁₀ H₁₃ N₃ O₄ (239.23): C, 44.28; H, 4.83; N,15.49. Found: C, 44.58; H, 5.17; N, 15.28.

Example 62 Methyl β-L-arabinopyranoside (81)

To a suspension of L-arabinose (100 g, 667 mmol) in anhydrous MeOH (450mL) was added a HCl /MeOH solution (7.3 g dry HCl in 50 mL MeOH) at roomtemperature under argon atmosphere. The mixture was refluxed for 2 h andcooled down to room temperature. The solution was concentrated to about3/4 of its volume to give a suspension. The solid precipitated wasfiltered and washed with cold MeOH (20 mL) to give the first crop as acrystalline powder (35.23 g). The filtrate was concentrated (35° C.) to1/4 of its volume. The solid precipitated was filtered, washed and driedas above to give the second crop (9.66 g) as a colorless crystallinepowder. The concentration and filtration were repeated to affordadditional 28.31 g of the product (total 73.2 g, 67%). ¹ H NMR (D₂ O) δ3.30 (s, OCH₃, 3H), 3.56 (dd, 1H, H₅), 3.73 (m, 1H, H₄), 3.77 (dd, 1H,H₅), 3.82 (bs, 1H, H₂), 4.73 (m, 1H, H₁).

Example 63 Methyl 3,4-isopropylidene-β-L-arabino-pyranoside (82)

To the mixture of methyl β-L-arabinopyranoside 81 (23.33 g, 142.26 mmol)and dimethoxypropane (55 mL, 448 mmol) in dry DMF (185 mL) was addedAmberlyst 15 (H⁺ form, 1.42 g) and the suspension was stirred at roomtemperature for 18 h. The solution was evaporated to give a syrup, whichwas dissolved in EtOAc (200 mL) and washed with brine (50 mL), sat.NaHCO₃ solution and brine (20 mL). The aqueous washings were combinedand extracted with EtOAc (5×20 mL), which was washed with NaCl/H₂ O andcombined with the organic solution. The EtOAc solution was dried overanhydrous Na₂ SO₄ and evaporated to dryness to give a syrup (29.2 g,quant.). ¹ H NMR (CDCl₃) δ 1.36 and 1.53 (2s, 6H, isopropylidene-CH₃),2.43 (d, 1H, 2'-OH), 3.44 (s, 3H, OCH₃), 3.78 (m, 1H, H₂), 3.93 (s, 2H,H₅), 4.15-4.25 (m, 2H, H₃ & H₄), 4.71 (d, 1H, H₁).

Example 64 Methyl3,4-isopropylidene-2-o-[(methylthio)thiocarbonyl]-β-L-arabino-pyranoside(83)

The above syrup 82 (29.2 g, 142.26 mmol) was dissolved in anhydrous THF(190 mL) and cooled to 0° C. To the solution was added NaH (55-65%, 6.9g, 172.5 mmol) slowly under argon atmosphere. The suspension wasrefluxed for 2 h and cooled to 0° C. To the mixture was added carbondisulfide (21 mL, 349.14 mmol) and the resultant dark mixture wasstirred at room temperature for 2 h. To the mixture was added methyliodide (12.4 mL, 160.64 mmol) at 0° C. and the mixture was stirred for16 h. The mixture was poured into ice-water (300 mL) and extracted withEtOAc (3×50 mL). The EtOAc solution was dried and evaporated untilcrystals precipitated. The suspension was left in a refrigerator for 16h. The crystals were filtered and washed with hexane to give the firstcrop (21.61 g) as a yellowish powder. The filtrate was concentrated,kept at 0° C. overnight and filtered to give the second crop (16.51 g).This was repeated two more times to give additional 1.44 g of theproduct (39.62 g, two steps from 81 94.7%). Mp 127-130° C. ¹ H NMR(CDCl₃) δ 1.39 and 1.55 (2s, 6H, isopropylidene-CH₃), 2.60 (s, 3H,SCH₃,), 3.40 (s, 3H, OCH₃), 4.01 (s, 2H, H₅), 4.30 (m, 1H, H₄), 4.50(dd, 1H, H₃), 4.98 (d, 1H, H₁), 5.78 (dd, 1H, H₂),

Example 65 Methyl 2-deoxy-β-L-erythro-pentopyranoside (84)

Compound 83 (40 g, 136 mmol) and AIBN (24.61 g, 150 mmol) were dissolvedin dry dioxane (400 mL) by heating in an oil bath (100° C.). The mixturewas bubbled with argon atmosphere at 100° C. for 15 min followed byaddition of diphenylsilane (51.4 mL, 272 mmol). The temperature of theoil bath was raised to 130° C. and the mixture was refluxed for 16 h.Additional diphenylsilane (2 mL, 10.8 mmol) and AIBN (1.27 g, 7.7 mmol)were added and refluxing was continued for additional 5 h. AdditionalAIBN (0.2 g, 1.2 mmol) was added and refluxing was continued foradditional 1 h. The mixture was cooled and evaporated to give compound84 as a syrup, which was mixed with 80% HOAc (544 mL) and stirred atroom temperature for 16 h. The mixture was evaporated to give a syrupwhich was partitioned between water and ether. The aqueous layer waswashed with ether and the combined organic layer was extracted withwater. The aqueous solution was evaporated to give compound 85 as asyrup (16.36 g, 81.4% for two steps from 83). ¹ H NMR (CDCl₃) δ), 1.89(dd, 2H, H₂). 2.30 (d,1H, OH), 2.47 (d, 1H, OH), 3.35 (s, 3H, OCH₃,),3.88-3.69 (m, 3H, H₄ & H₅), 4.03 (m, 1H, H₃), 4.79 (t, 1H, H₁).

Example 66 2'-deoxy-β-L-erythro-pentose (86)

Compound 85 (16.36 g, 110.5 mmol) was dissolved in 0.8 M HCl aqueoussolution (546 mL) and the resultant mixture was stirred at roomtemperature for 72 h. The mixture was neutralized with 1N NaOH aqueoussolution to PH 6-7 and was evaporated to give a syrup. The crude waspurified on a silica gel column (4×15 cm) eluted with CH₂ Cl₂ /MeOH(1:0to 95:5) The proper fractions were evaporated to give compound 86 as asyrup (10.53 g, 71.1%).

Example 67 Methyl 2'-deoxy-β-L-erythro-pentose (87)

Compound 86 (15.68 g, 117.0 mmol) was dissolved in dry MeOH (342 mL) andto the resultant solution was added 1% HCl/MeOH (35 mL). The solutionwas kept at ROOM TEMPERATURE for 1 h and neutralized with Py (55 mL) at5° C. to PH ˜6. The mixture was evaporated with silica gel and purifiedon a silica gel column (1×5 cm) eluted with CH₂ Cl₂ /MeOH(98:2 to 96:4)to give compound 87 as a syrup (13.94 g, 80.5%). ¹ H NMR (CDCl₃) δ2.22-2.44 (m, 2H, 11₂), 3.50 and 3.59 (2s, 3H, OCH₃), 3.75-3.88 (m, 2H,H₅), 4.26 (m, 1H, H₄), 4.66 (m, 1H, H₃), 5.25 (t, 1H, H₁).

Example 68 Methyl 2'-deoxy-3,5-di-O-p-toluoyl-L-erythro-pentose (88)

Compound 87 (9.00 g, 60.8 mmol) was dissolved in pyridine (180 mL) andcooled in an ice-water bath. To this cold solution was added toluoylchloride (18 mL, 00 mmol) in 30 min and the resultant solution wasstirred at room temperature for 16 h. The mixture was evaporated todryness. The mixture was extracted with EtOAc, washed with brine, driedand evaporated. The crude product was purified on a silica gel column(3×15 cm) using hexane/EtOAc (1:0 to 5:1) as the eluent. Evaporation ofthe proper fractions gave compound 88 as a syrup (22.63 g, 97%). ¹ H NMR(CDCl₃) δ 2.40 (2s, 6H, 2×CH₃), 3.35 (s, 3H, OCH₃ of β-anomer), 3.41 (s,3H, OCH of α-anomer), 4.6-4.5 (m, H₄ and H₅ of both anomers), 5.19 (d,1H, H₁ of α-anomer), 5.21 (dd, 1H, H₁ of β-anomer), 5.41 (m, 1H, H₃ ofα-anomer), 5.59 (m, 1H, H₃ of β-anomer), 7.18-8.02 (m, 8H, Aromatic),

Example 68 2'-Deoxy-3',5'-di-O-p-toluoyl-α-L-erythro-pentofuranosylchloride(13)

Compound 88 (22 g, 57.3 mmol) was dissolved in dry ether (200 mL) andthe solution was cooled to 0° C. in an ice bath. To the solution wasbubbled dry HCl for ˜5 min until the mixture crystallized. The reactionmixture was then kept in a refrigerator overnight. The solid thatprecipitated was filtered and washed with cold ether. The solid wasimmediately dried under vacuum over NaOH to give compound 13 as acolorless crystalline powder (19.28 g). The filtrate was concentratedand treated with HCl and kept in a refrigerator overnight. Filtration,washing and drying gave additional 1.2 g of product (total 20.48 g,92%), mp 118-121° C. ¹ H NMR (CDCl₃) δ 2.39 (2s, 6H, aromatic-CH₃), 2.82(m, 2H, H₂), 4.65 (m, 2H, H₅), 4.86 (q, 1H, H₄), 5.57 (m, 1H, H₃), 6.48(d, 1H, H₁), 7.25 (2d, 4H, aromatic-H), 7.95 (2d, 4H, aromatic-H).

Example 69 Methyl1-(2'-deoxy-3',5'-di-O-p-toluoyl-β-L-erythro-pentofuranosyl)-1,2,4-triazole-5-carboxylate(89), Methyl1-(2'-deoxy-3',5'-di-O-p-toluoyl-β-L-erythro-pentofuranosyl)-1,2,4-triazole-2-carboxylate(90) and Methyl1-(2'-deoxy-3',5'-di-O-p-toluoyl-β-L-erythro-pentofuranosyl)-1,2,4-triazole-3-carboxylate (91)

To a solution of methyl 1,2,4-triazole-3-carboxylate (1.27 g, 10 mmol)in dry acetonitrile (50 mL) was added sodium hydride (60% in oil, 0.5 g,12.5 mmol). The mixture was stirred at room temperature for 30 min. Dryand powdered chloro sugar 13 was added and the suspension was stirred atroom temperature for 16 h. The mixture was evaporated to give a residuewhich was partitioned between water/EtOAc and extracted in EtOA. Theaqueous solution was extracted with EtOAc. The combined EtOAc solutionwas washed with brine and evaporated to dryness. The mixture waspurified on a silica gel column (3×20 cm) using EtOAc/hexane (1.2:1) asthe eluent to give 89 (1.72 g), 90 (0.98 g) and 91 (0.45 g).

¹ H NMR (CDCl₃) 89: δ 2.52 (2s, 6H, CH₃), 2.82 (m, 1H, H_(2')), 3.45 (m,1H, H_(2')), 4.60 (dd, 1H, H_(5')), 4.72 (dd, 1H, H_(5')), 4.76 (m, 1H,H₄,), 6.03 (m, 1H, H_(3')), 7.29-7.38 (m, 5H, aromatic-H and H_(1')),7.97-8.12 (m, 5H, aromatic-H and C₅ H). 90: δ 2.50 & 2.53 (2s, 6H, CH₃),2.95 (m, 1H, H_(2')), 3.20 (m, 1H, H₂,), 4.09 (s, 3H, OCH_(3')), 4.72(m, 3H, H_(4') & H_(5')), 5.83 (m 1H, H_(3')), 6.47 (t, 1H, H_(1')),7.36 (dd, 4H, aromatic-H), 8.02 (dd, 4H, aromatic-H), 8.51 (s, 1H, C₅H). 91: δ 2.53 (m, 7H, H_(2') & 2×CH₃), 3.16 (m, 1H, H_(2')), 4.13 (s,3H, OCH_(3')), 4.69-4.85 (m, 3H, H_(4') & H_(5')), 5.73 (m, 1H, H_(3')),6.88 (q, 1H, H_(1')), 7.35 (dd, 4H, aromatic-H), 7.94 & 8.05 (dd, 4H,aromatic-H), 8.76(s, 1H, C₅ H).

Example 701-(2'-Deoxy-β-L-erythro-pentofuranosyl)-1,2,4-triazole-5,-carboxamide(92)

A mixture of 89 (1.77 g, 3.70 mmol) and saturated methanolic ammoniasolution (40 mL) was heated in a steel bomb at 55° C. for 16 h. Aftercooling, the solution was evaporated with silica get and purified on asilica gel column eluted with CH₂ Cl₂ /MeOH (10:1) to give compound 92as a colorless powder (297 mg, 35%). ¹ H NMR (DMSO-d₆): δ 2.27 (m, ¹ H,H_(2')), 2.60 (m, 1H, H_(2')), 3.32 (m, 1H, H_(5')), 3.48 (m, 1H,H_(5')), 3.80 (m, 1H, H_(4')), 4.41 (m, 1H, H_(3')), 7.12 (t, 1H,H_(1')), 8.06 (s, 1H, NH), 8.14 (s, 1H, C₅ H), 8.27 (s, 1H, NH.

Example 711-(2'-Deoxy-β-L-erythro-pentofuranosyl)-1,2,4-triazole-3-carboxamide(93)

A mixture of 91 (0.45 g, 0.94 mmol) and saturated methanolic ammoniasolution (20 mL) was heated in a steel bomb at 55° C. for 16 h. Aftercooling, the solution was evaporated to dryness. The residue waspurified on a silica gel column using CH₂ Cl₂ /MeOH (10:1) as the eluentto give 93 (54 mg, 25%). ¹ H NMR (DMSO-d₆): δ 2.24 (m, 1H, H_(2')), 2.38(m, 1H, H_(2')), 3.61 (m, 2H, H_(5')), 3.85 (m, 1H, H_(4')), 4.30 (m,1H, H_(3')), 6.70 (t, 1H, H_(1')), 7.94 (s, 1H, N H), 8.33 (s, 1H, NH)8.98 (s, 1H, C₅ NH)

Example 721-(2'-Deoxy-3',5'-di-O-p-toluoyi-β-L-erythro-pentofuranosyl)-2,4-dicyanopyrrole(94)

To a solution of 2,4-dicyanopyrrole (302 mg, 2.58 mmol) in dryacetonitrile (25 mL) was added sodium hydride (60% in oil, 125 mg, 2.6mmol). The mixture was stirred at room temperature for 30 min. Thechloro sugar 13 (1 g, 2.58 mmol) was added and the suspension wasstirred at room temperature for 16 h. The mixture was evaporated to givea solid residue which was partitioned between water and EtOAc. Theaqueous solution was extracted with EtOAc. The combined EtOAc extractwas washed with water and brine, dried and evaporated to dryness. Theproduct was purified on silica gel column (3×20 cm) using hexane /EtOAc(5:2) as eluent to give 94 as an oil (605 mg, 50%). ¹ H NMR (CDCl₃): δ2.29 (s, 3H, aromatic-CH₃), 2.55 (s, 3H, aromatic-CH₃), 2.67 (m, 1H,H_(2')), 2.98 (m, 1H, H_(2')), 4.74-4.89 (m, 3H, H_(4') & H_(5')),5.77(m, 1H, H_(3')), 6.36 (t, 1H, H_(1')), 7.18 (s, 1H, C₅ H), 7.38 (m,4H, aromatic-H, 7.68 (s, 1H, C₃ H), 7.97 (d, 2H, aromatic-H), 8.05 (d,2H, aromatic-H).

Example 73 1-(2'-Deoxy-β-L-eiythro-pentofutranosyl)-2,4-dicyanopyrrole(9)

A mixture of 94 (605 mg, 1.29 mmol) and saturated methanolic ammoniasolution (20 mL) was heated in a steel bomb at 65° C. for 16 h. Aftercooling, the solution was evaporated to dryness. The crude product waspurified on a silica gel column eluted with CH₂ Cl₂ /MeOH (10:1) to give95 (158 mg, 52%). ¹ H NMR (CD₃ OD): δ 2.55 (m, 2H, H_(2')), 3.82 (m, 2H,H_(5')), 4.08 (m, 1H, H_(4')), 4.53 (m, 1H, H_(3')), 6.38 (t, 1H,H_(1')), 7.37 (s, 1H, C₅ H), 8.19 (s, 1H, C₃ H).

Example 741-(2'-Deoxy-β-L-erythro-pentofuranosyl)pyrrole-2,4-dicarboxamide (96)

To a solution of 95 (90 mg, 0.385 mmol) in aqueous NH₄ OH solution(29.6%, 9 mL) was added H₂ O₂. The solution was stirred at roomtemperature for 2 h and evaporated to dryness. The residue was purifiedon a silica gel column eluted with CH₂ C₂ /MeOH (10:1) to give Compound96 (75 mg, 72%). ¹ H NMR (CD₃ OD): δ 2.31 & 2.61 ((, 2H, H_(2')), 3.89(m, 2H, H_(5')), 4.04 (m, 1H, H_(4')), 4.45 (m, 1H, H_(3')), 6.93 (t,1H, H_(3')), 7.24 (s, 1H, C₅ H), 8.09 (s, 1H, C₃ H).

Example 75 Methyl1-(2'-deoxy-3,',5'-di-O-p-toluoyi-β-L-erythro-pentofuranosyl)pyrazole-3,5-dicarboxylate(97)

To a solution of methyl pyrazole-3,5-dicarboxylate (458 mg, 2.5 mmol) indry acetonitrile (25 mL) was added sodium hydride (60% in oil, 144 mg,3.0 mmol). The mixture was stirred at room temperature for 30 min. Thechloro sugar 13 (970 mg, ˜95%, 2.5 mmol) was added and the suspensionwas stirred at room temperature for 4 h. The mixture was evaporated todryness and the residue was purified on silica gel column (3×7 cm) usinghexane /EtOAc (5:2) as the eluent to give 97 as an oil (470 mg, 35%). ¹H NMR (CDCl₃): δ 2.40 (d, 6H, aromatic-CH₃), 2.70 (m, 1H, H_(2')), 3.60(m, 1H, H_(2')), 3.93 (d, 6H, OCH₃), 4.48-4.65 (m, 3H, H_(4') & H_(5')),5.89(m, 1H, H_(3')), 7.18-7.29 (m, 5H, aromatic-H & H_(1')), 7.38 (s,1H, C₄ H), 7.90 (m, 4H, aromatic-H).

Example 761-(2'-Deoxy-β-L-erythro-pentofuranosyl)pyrazole-3,5-dicarboxamide (98)

A mixture of 97 (270 mg, 0.51 mmol) and saturated methanolic ammoniasolution (20 mL) was heated in a steel bomb at 100° C. for 16 h. Aftercooling, the solution was evaporated and purified on a silica gel columnusing CH₂ Cl₂ /MeOH (10:1) to give 98 as a colorless powder (189 mg,73%). ¹ H NMR (DMSO-d₆): δ 2.25 (m, 1H, H_(2')), 2.89 (m, 1H, H_(2')),3.42 (m, 1H, H_(5')), 3.59 (m, 1H, H_(5')), 3.86 (q, 1H, H_(4')), 4.55(m, 1H, H_(3')), 4.77 (t, 1H, OH), 5.27 (d, 1H, OH), 7.17 (t, 1H,H_(1')), 7.29 (s, 1H, C₄ H), 7.51 (s, 1H, NH), 7.66 (s, 1H, NH), 7.80(s, 1H, NH), 8.19 (s, 1H, NH).

Example 77 Methyl1-(2'-deoxy-3',5'-di-O-p-toluoyl-β-L-erythro-pentofuranosyl)pyrazole-4-carboxylate(99)

To a solution of methyl pyrazole-4-carboxylate (315 mg, 2.5 mmol) in dryacetonitrile (30 mL) was added sodium hydride (60% in oil, 144 mg, 3.0mmol). The mixture was stirred at 50° C. for 15 min. The chloro sugar 13(1 g, ˜95%, 2.5 mmol) was added and the suspension was stirred at roomtemperature for 2 h. The mixture was evaporated to give a residue whichwas partitioned between water and EtOAc. The aqueous solution wasextracted with EtOAc. The combined EtOAc extract was washed with waterand brine, dried over NaSO₄ and evaporated to dryness. The residue waspurified on silica gel column (3×12 cm) using hexane /EtOAc (4:1) togive 99 as a crystalline powder (549 mg, 46%). ¹ H NMR (CDCl₃): δ 2.40(d, 6H, aromatic-CH₃), 2.72 (m, 1H, H_(2')), 3.16 (m, 1H, H_(2')), 3.79(d, 3H, OCH₃), 4.51-4.62 (m, 3H, H_(4') & H_(5')), 5.77 (m, 1H, H_(3')),6.20 (t, 1H, H_(1')), 7.24 (m, 4H, aromatic-H), 7.92 (m, 5H, aromatic-H& C₅ H), 8.10 (s, 1H, C₃ H).

Example 78 1-(2'-Deoxy-β-L-erythro-pentofuranosyl)pyrazole-4-carboxamide(100)

A mixture of 99 (500 mg, 1.046 mmol) and saturated methanolic ammoniasolution (30 mL) was heated in a steel bomb at 100° C. for 16 h. Aftercooling, the solution was evaporated and the residue was purified on asilica gel column using CH₂ Cl₂ /MeOH (10:1) to give 100 as yellow foam(50 mg, 20%). ¹ H NMR (DMSO-d₆): δ 2.30 (m, 1H, H₂,), 2.56 (m, 1H,H_(2')), 3.41-3.56 (m, 2H, H_(5')), 3.84 (m, 1H, H_(4')), 4.36 (m, 1H,H_(3')), 4.88 (bs, 1H, OH), 5.32 (bs, 1H, OH), 6.11 (t, 1H, H_(1')),7.08 (s, 1H, NH), 7.63 (s, 1H, NH), 7.90 (d, 1H, C₅ H), 8.36 (d, 1H, C₃H). 7.80 (s, 1H, NH), 8.19 (s, 1H, NH).

Example 79 Methyl-α-L-lyxopyranoside (102)

To a methanolic HCl solution [600 mL, 0.5% w/v, prepared in situ byreaction of acetyl chloride (6.0 mL)] was added L-lyxose (101, 118 g,786 mmol) and refluxed for 5 h [the reaction was complete in 4 h (by TLC30% MeOH/CH₂ Cl₂) and continued for additional 1 h (total 5 h)] underexclusion of moisture (protected by CaCl₂ guard tube). The reactionmixture was neutralized with pre-treated¹ amberlite basic resin IRA 410(100.0 g) for 10 min under stirring. The resin was filtered and washedwith methanol (3×50 mL). The combined washings were evaporated to obtaina color less syrup. The syrup was co-evaporated with ethyl acetate (2×50mL) and finally recrystallized (by scratching the side of RB flask orsonication) from ethyl acetate (500 mL) to obtain white crystallineproduct 102 (87 g, 67% total from both 1 and 2 crops). ¹ H NMR (300 MHz,(CD₃)₂ CO): δ 3.15 (bs, 3H, OH), 3.41 (s, 3H, OCH₃), 3.48 (m, 1H),3.66-3.72 (m, 2H), 3.73-3.87 (m, 2H), 4.64 (d, 1H, H_(-5'), J=2.7 Hz).

Example 80 Methyl-2,3-O-isopropylidene-α-L-lyxopyranoside (103)

To a suspension of 102 (69 g, 420.0 mmol) in a mixture of 2,2-dimethoxypropane (200.0 mL) and anhydrous acetone (200.0 mL) was added a solution(4M) of HCl in dioxane (4.0 mL) and the reaction mixture was stirred at25° C. for 16 h. TLC (50% ethyl acetate/CH₂ Cl₂) of the reactionindicated the complete conversion of the starting material. The reactionwas quenched with solid sodium bicarbonate (500 mg) and filtered. Thefiltrate was evaporated and the oily residue (pinkish) that obtained waspurified by silica gel flash chromatography using CH₂ Cl₂ /ethyl acetate(100/0 to 80/20, in 5% increments) as the eluent to obtain the product103 (80 g, 93.2%).). ¹ H NMR (300 MHz, (CDCl₃): δ 1.31 (s, 3H), 1.47 (s,3H), 2.95 (bs, 1H), 3.41 (s, 3H), 3.66-3.77 (m, 3H), 4.07 (dd, 1H,J=6.04 & 2.75 Hz), 4.16 (t, 1H, J=6.04 & 4.67 Hz), 4.60 (d, 1H,J=2.74Hz).

Example 81 Methyl-4-azido-4-deoxy-2,3-O-isopropylidene-β-D-ribopyranoside (104)

To a mixture of pyridine (6.4 mL, 79.65 mmol) and dimethylamino pyridine(100 mg, 0.72 mmol) in anhydrous CH₂ Cl₂ (400 mL) was slowly addedtrifluoromethanesulfonic anhydride (11.82 mL, 71.68 mmol) at -20° C. Themixture was stirred at -20° C. for 5 min and was then added a solutionof 103 (5.0 g, 24.50 mmol) in CH₂ Cl₂ (50.0 mL). The reaction mixturewas stirred at -20° C. for 15 min. It was then poured into a mixture ofice-water (500 mL) and the organic layer separated. The aqueous phasewas extracted with CH₂ Cl₂ (2×100 mL). The combined organic layer waswashed with brine (500 mL), dried (NaSO₄) and evaporated to obtain theproduct as pale yellow gummy solid (14 g).

To a solution of abovemethyl-4-O-trifluoromethanesulfonyl-2,3-O-isopropylidene-β-L-lyxopyranosidein a mixture of DMF (350 mL) and tetramethyl urea (50 mL) was addedsodium azide (30.0 g, 461.53 mmol, 18.83 eq) at 0-5° C. (ice-water bath)and stirred at 23° C. for 3 h. The volatiles were evaporated and theresidue was diluted with CH₂ Cl₂ (500 mL) and water (200 mL). Thcorganic layer was separated and washed with water (2×250 mL) and brine(300 mL), dried (NaSO₄) and evaporated to obtain an oily residue whichwas purified by flash silica gel chromatography using hexane/ethylacetate (100/0; 97.5/2.5; and 95/5) as the eluent to obtain the product104 (2.8 g, 49.88% for the two steps).¹ H NMR (300 MHz, (CDCl₃): δ 1.36(s, 3H, CH₃), 1.54 (s, 3H , CH₃),3.42 (s, 3H, OCH₃), 3.7-3.9 (m, 3H),4.01 (dd, 1H, J=6.05 & 3.85 Hz), 4.48 (d, H, J=3.85 H z), 4.51 (m, 1H).

Example 82 N-Acetyl-4-amino-4-deoxy-2,3-O-isopropylidene-β-D-methyl-ribopyranoside (105)

To a solution of 104 (6.5 g, 28.38 mmol) in MeOH (50.0 mL) was addedNaHCO₃ (2.38 g, 28.38 mmol) followed by Pd/C (5% w/w, 650 mg). Thereaction mixture was shaken well under H₂ (40 psi) atmosphere at roomtemperature for 1 h. The TLC (30% ethyl acetate/hexane) indicatedcompletion of the reaction. The reaction mixture was filtered overcelite bed and the filtrate was evaporated to dryness. The residue wasco-evaporated with toluene (2×20 mL) and pyridine (2×20 mL). Theresulting residue was then carried forward to the next reaction withoutfurther purification.

To a mixture of the above residue (5.76 g, crude from the abovereaction) and DMAP (0.059 g, 0.425 mmol) in pyridine (6.8 mL, 84.5 mmol)was added acetic anhydride (4.01 mL, 42.57 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 h. The TLC (100% ethylacetate) indicated completion of the reaction. MeOH (1.0 mL) was addedand the volatiles were evaporated. The residue was dissolved in CH₂ Cl₂(300 mL) and this solution was then washed with cold and dil. HCl (0.5M,3×200 mL), sat. NaHCO₃ (200 mL) and brine (200 mL), dried (Na₂ SO₄) andevaporated. The residue that obtained was purified by flashchromatography over silica gel using ethyl acetate/hexane (0/100 to10/90 to 20/80 to 50/50 to 100/0) as the eluent to obtain the product105 (in a combined yield of 3.76 g, 54.11%).¹ H NMR (300 MHz, (CDCl₃): δ1.35 (s, 3H, CH₃), 1.51 (s, 3H, CH₃), 2.0 (s, 3H, COCH₃), 3.37 (t, 1H),3.45 (s, 3H, OCH₃), 3.85 (dd, 1H), 4.05 (dd, 1H), 4.38 (dd, 1H), 4.40(d, 1H, J=4.5 Hz), 4.58 (m, 1H), 5.78 (bd, 1H),.

Example 83 1,2,3,5-Tetra-O-acetyl-4-deoxy-4-(acetamido)-D-ribofuranose(106)

A solution of 105 (5.0 g, 20.40 mmol) in a mixture of distilled waterand AcOH (1:1, 50 mL) was heated at 70-75° C. for 1.5 h. The TLC (100%ethyl acetate) indicated completion of the reaction. Absolute EtOH (2×30mL) was added and co-evaporated the volatiles to obtain a dry solidresidue. To this solid was added a mixture of glacial acetic acid andacetic anhydride (50 mL, 1:1) and cooled to 0° C., and treated withconc. H₂ SO₄ (1.5 mL). The reaction mixture was stirred at 0° C. for 30min and then kept at 4° C. for 2 days. The reaction mixture was treatedwith anhy. NaOAc (15.0 g) and stirred at roo temperature for 30 min. Thereaction mixture was then poured into ice-water mixture (300 mL) andextracted with CH₂ Cl₂ ((2×250 mL). The combined organic layer waswished with water (2×250 mL) and brine (400 mL), dried (Na₂ SO₄) andevaporated. The crude residue that obtained was purified by flashchromatography over silica gel using MeOH/CH₂ Cl₂ (0/100 to 3/97) as theeluent to give pure product 106 (3.71 g, 50.82%). ¹ H NMR (300 MHz,(CDCl₃): δ 1.99-2.11 (m, 15H, 5xCH₃), 4.17-4.5 (m, 3H), 5.27-5.52 (m,2H), 6.35 (s, 0.75H), 6.53 (d, 0.25H, J=4.8 Hz).

Example 84Methyl-1-(2',3',5'-tri-O-acetyl-4'-deoxy-4'-acetamido-p-D-ribofuranosyl)-1,2,4-triazole-3-carboxylate(107)

A suspension of methyl-1,2,4-triazole-3-carboxylate (1.77 g, 13.97 mmol)and ammonium sulphate (177 mg) in hexamethyldisilazane (40 mL) wasrefluxed for 2.5 h under N₂ atmosphere. The reaction mixture wasevaporated to dryness and the residue was suspended in1,2-dichloroethane (50 mL). It was then treated with a solution of 106(4.4 g, 12.25 mmol) in 1,2-dichloroethane (50 mL). To the reactionmixture was then added fuming SnCl₄ (1.63 mL, 13.97 mmol) at 0-5° C.(ice-water bath) and stirred at room temperature for 1 h. The reactionmixture was carefully quenched with saturated solution of NaHCO₃ (50 mL)and then diluted with CH₂ Cl₂ (200 mL). The mixture was filtered over acelite bed (5 g) and washed with CH₂ Cl₂ (100 mL). The organic layer ofthe filtrate was separated and the aqueous layer was extracted with CH₂Cl₂ (2×100 mL). The combined organic layer was washed with water (2×300mL) and brine (500 mL), dried (Na₂ SO₄) and evaporated. The cruderesidue that obtained was recrystallized from ethyl acetate (40 mL) toobtain pure titled product 107 (2.7 g, 51.71%). ¹ H NMR (300 MHz,(CDCl₃): δ 2.03-2.15 (m, 12H, 4xCOCH₃), 3.95 (s, 3H, OCH₃), 4.2 (m, 1H,H_(5')), 4.43 (m, 2H, H_(4') & H_(5')), 5.65 (dd, 1H, H_(3'), J=4.67 &1.1 Hz), 6.17 (t, 1H, H_(2'), J=4.67 & 6.04 Hz), 6.28 (d, 1H, H_(1'),J=6.04 Hz), 8.47 (s, 0.86H, major rotamer, C₅ H), 8.60 (s, 0.14H, minorrotamer, C₅ H). Anal. Calcd. for C₁₇ H₂₂ N₄ O₉ : C, 47.89; H, 5.20; N.13.14. Found: C, 47.93; H, 5.40; N, 13.27.

Example 851-(4'-Deoxy-4'-acetamido-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide(108)

A solution of 107 (2.7 g, 6.33 mmol) in saturated methanolic ammonia(100 mL) was stirred at room temperature in steel bomb for 16 h. Thereaction mixture was evaporated to dryness and the residue that obtainedwas purified by flash chromatography over alumina using the solventmixture ethyl acetate/n-propyl alcohol/water (64/4/32 to 57/14/29%,lower layer) as the eluent to afford the titled product 108 (1.7 g). Theproduct was wet ˜5% with ethyl alcohol and also contaminated littleacetamide. ¹ H NMR (300 MHz, CD₃ OD): δ 1.87 (s, 0.86H, COCH₃, minorrotamer (min)), 2.14 (s, 2.14H, COCH₃, major rotamer (maj)), 3.87 (d,2H, H_(5'), J=6.59 Hz), 4.1-4.01 (m, 1H, H₄), 4.26 (d, 0.75H, J=4.12 Hz,H_(3'),maj), 4.31 (t, 0.25H, J=3.8 Hz, H_(3'), min), 4.54 (t, 0.25H,J=4.1 Hz, H_(2'), min), 4.85 (dd, 0.75H, J=4.4 & 6.05 Hz, H_(2'), maj),6.03 (d, 0.75H, J=6.04 Hz, H_(1'), maj), 6.81 (d, 0.25H, J=4.13 Hz,H_(1'), min), 8.69 (s, 0.75H, C₅ H, maj), 8.95 (s, 0.25H, C₅ H, min).Anal. Calcd. for C₁₀ H₁₅ N₅ O₅ : C, 42.10; H, 5.30; N. 24.55. Found: C,42.21; H, 5.19; N, 24.23.

Example 861-[(3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide(109)

A suspension of 108 (0.7 g, 2.45 mmol) in pyridine (15 mL) was treatedwith 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (1.06 mL, 3.31 mmol)and stirred at room temperature for 16 h. The reaction mixture wascarefully quenched with saturated solution of NaHCO₃ (5 mL) and dilutedwith CH₂ Cl₂ (100 mL). The organic layer was separated and the aqueouslayer was extracted with CH₂ Cl₂ (2×25 mL). The combined organic layerwas washed with water (2×100 mL) and brine (100 mL), dried (Na₂ SO₄) andevaporated. The crude residue was purified by flash chromatography oversilica gel using CHCl₃ /MeOH (100/0-98/2-95/5-90/10) as the eluent toafford 109 (0.7 g, 54%). H NMR (300 MHz, CDCl₃): δ 0.93-1.18 (m, 24H),1.38 (m, 2H), 2.02 (s, 0.84H, COCH₃, minor rotamer (min)), 2.15 (s,2.16H, COCH₃, major rotamer (maj)), 3.83 (m, 1H, H_(5')), 3.98-4.13 (m,1H, H_(5')), 4.33 (d, 0.34H, J=3.85 Hz, H_(2'), min), 4.42 (d, 0.66H,J=4.67 Hz, H_(2'), maj), 4.52 (dd, 0.34H, H_(4'), min), 4.65 (dd, 0.66H,H_(4'), maj), 5.29 (t, 1H, J=4.97 Hz, H_(3')), 5.80 (bs, 0.66H, maj),5.94 (bs, 0.34H, min), 5.99 (s, 0.34H, H_(1'), min), 6.40 (s, 0.66H,H_(1'), maj), 6.91 (bs, 0.66H, maj), 7.01 (bs, 0.34H, min), 8.37 (s,0.66H, C₅ H, maj), 8.53 (s, 0.34H, C₅ H, min).

Example 871-[2'-O-(p-Tolylthionoformyl)-3',5'-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide(110)

To a solution of 109 (0.6 g, 1.138 mmol) in a mixture of CH₂ Cl₂ (9 mL)and pyridine (1 mL) was added O-(p-tolyl)thionochloroformate (0.219 mL,1.42 mmol) and the reaction mixture was stirred at room temperature for16 h. The reaction mixture was quenched with saturated solution ofNaHCO₃ (5 mL) and diluted with CH₂ Cl₂ (100 mL). The organic layer wasseparated and the aqueous layer was extracted with CH₂ Cl₂ (2×25 mL).The combined organic layer was washed with water (2×100 mL) and brine(100 mL), dried (Na₂ SO₄) and evaporated. The crude residue was purifiedby flash chromatography over silica gel using CHCl₃ /ethyl acetate(100/0-95/5-90/10) as the eluent to afford pure product 110 (0.35 g,45%). H NMR (300 MHz, CDCl₃): δ 1.04-1.15 (m, 24H), 1.32 (m, 2H), 2.01(s, 1H, COCH₃, minor rotamer (min)), 2.19 (s, 2H, COCH₃, major rotamer(maj)), 2.35 (s, 3H, CH₃), 3.92 (m, 1H, H₅.), 4.05 (m, 1H, H_(5')),4.68-4.81 (m, 1H, H_(4')), 5.5 (t, 1H, J=6.05 & 5.22 Hz, H_(3')), 5.75(bs, 0.66H, maj), 5.88 (bs, 0.34H, min), 6.10 (d, 1 H, J=4.67 Hz,H_(2')), 6.17 (s, 0.34H, H_(1'), min), 6.54 (s, 0.66H, H_(1'), maj),6.87 (bs, 0.66H, maj), 6.96 (d, 2H, J=8.24 Hz, aromatic-H), 6.98 (bs,0.34H, min), 7.20 (d, 2H, J=8.24 Hz), 8.40 (s, 0.66H, C₅ H, maj), 8.68(s, 0.34H, C₅ H, min).

Example 881-[(3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-2',4'-dideoxy-4'-acetamido-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide(111)

A solution of 110 (0.35 g, 0.516 mmol) in toluene (20 mL) was purgedwith argon for 20 min and then treated with 2,2'-azobisisobutyronitrile(0.084 g, 0.516 mmol) and tributyltin hydride (0.274 mL, 1.03 mmol). Thereaction mixture was refluxed for 3 h under a stream of argon. Thereaction mixture was evaporated to dryness and the crude residue waspurified by flash chromatography over silica gel using CHCl₃ /ethylacetate (100/0-90/10-70/30-40/60-20/80-0/100) as the eluent to affordthe product 111 (0.23 g, 87%). ¹ H NMR (300 MHz, CDCl₃): δ 0.95-1.15 (m,24H), 1.24 (m, 2H), 2.0 (s, 0.9H, COCH₃, minor rotamer (min)), 2.13 (s,2.1H, COCH₃, major rotamer (maj)), 2.36-2.58 (m, 1H, H_(2')), 2.84 (m,1H, H_(2')), 3.74-3.92 (m, 2H, H_(5')), 4.11 (m, 0.66H, H_(4'), maj),4.49-4.67 (m, 0.34H, H_(4'), min), 5.3 (m, 1H, H_(3')), 5.88 (bs, 0.66H,maj), 6.01 (bs, 0.34H, min), 6.14 (d, 0.34H, J=6.02 Hz, H_(1'), min),6.54 (d, 0.66H, J=7.97 Hz, H_(1'), maj), 6.89 (bs, 0.66H, maj), 7.03(bs, 0.34H, min), 8.35 (s, 0.66H, C₅ H, maj), 8.55 (s, 0.34H, C₅ H,min).

Example 891-(2',4'-Dideoxy-4'-acetamido-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide(112)

A solution of 111 (0.23 g, 0.45 mmol) in CH₂ Cl₂ (5 mL) was treated withtriethylamine trishydrofluoride (0.29 mL, 1.79 mmol) at roomtemperature. The reaction mixture was stirred for 48 h at roomtemperature. The volatiles were removed and the residue was purified byflash chromatography over silica gel using CHCl₃ /MeOH(100/0-95/5-90/10) as the eluent to afford pure product 112 (0.08 g,66%). ¹ H NMR (300 MHz, CD₃ OD): δ 1.95 (s, 0.36H, COCH₃, minor rotamer(min)), 2.16 (s, 2.64H, CH₃, major rotamer (maj)), 2.51(m, 1H, H_(2')),2.87 (m, 1H, H_(2')), 3.82 (m, 2H, H_(5')), 3.99 (t, 1H, J=6.87 Hz,H_(4')), 4.44 (d, 1H, J=4.12 Hz, H_(3')), 6.54 (t, 1H, J=7.69 Hz,H_(1')), 8.63 (s, 0.88H, C₅ H, maj), 8.88 (s, 0.12H, C₅ H, min). Anal.Calcd. for C₁₀ H₁₅ N₅ O₄ : C, 44.60; H, 5.62; N, 26.01. Found: C, 44.71;H, 5.69; N, 25.98.

Example 90 Methyl-2,3-O-isopropylidene-α-D-lyxopyranoside (115)

To a methanolic HCl solution [500 mL, 0.5% w/v, prepared in situ byreaction of acetyl chloride (5 mL, 70.37 mmol) with MeOH(Fisher HPLCgrade)] was added D-lyxose (113, 100 g, 666.66 mmol) and refluxed for 5h under N₂ atmosphere. The reaction mixture was neutralized withpre-treated¹ amberlite basic resin IRA-410 (100.0 g) for 10 min understirring. The resin was filtered and washed with methanol (3×125 mL).The combined washings were evaporated to obtain a color less syrup ofmethyl-β-D-lyxopyranoside (114, 110 g, a quantitative yield) which wascarried forward for the next reaction without further purification

Note:

Preparation of pre-treated Amberlite Resin IRA-410: The resin (100 g)was treated with aq. NaOH (0.5M, 200 mL) for 15 min. Under stirring andfiltered and washed with deionized water (4×300 mL) until the pH ofwashings showed neutral to pH paper. Finally the resin was washed withanhydrous MeOH (3×30 mL) and used immediately.

To a suspension of 114 (110 g, 666.66 mmol) in a mixture of2,2-dimethoxy propane (400.0 mL) and anhydrous acetone (400.0 mL) wasadded a solution (4M) of HCl in dioxane (8.0 mL) and the reactionmixture was stirred at 25° C. for 16 h. The TLC (50% ethyl acetate/CH₂Cl₂) indicated completion of the reaction. The reaction was quenchedwith solid sodium bicarbonate (500 mg) and filtered. The filtrate wasevaporated and the oily residue (pinkish) was purified by silica gelflash chromatography using CH₂ Cl₂ /ethyl acetate (100/0 to 80/20, with5% increments) as the eluent to obtain 115 (63.97%, 87 g, overall yieldfor both the steps).

Example 91Methyl-4-azido-4-deoxy-2,3-O-isopropylidene-β-L-ribopyranoside(116)

To a mixture of pyridine (6.432 mL, 79.9 mmol) and dimethylaminopyridine (105 mg, 0.75 mmol) in anhydrous CH₂ Cl₂ (600 mL) was slowlyadded trifluoromethanesulfonic anhydride (10.72 mL, 65 mmol) at -20° C.The mixture was stirred at -20° C. for 5 min and then added a solutionof 115 (10.2 g, 50 mmol) in CH₂ Cl₂ (100.0 mL), and the reaction mixturestirred at -20° C. for 15 min. The TLC (15% ethyl acetate/hexane)indicated completion of the reaction. The reaction mixture was pouredinto a mixture of ice-water (500 mL) and the organic layer wasseparated. The aqueous phase was extracted with CH₂ Cl₂ (2×100 mL). Thecombined organic layer was washed with water (2×250 mL) and brine (500mL), dried (NaSO₄) and evaporated to obtain the intermediate triflateproduct as a pale yellow gummy solid (16 g).

To a solution of abovemethyl-4-O-trifluoromethanesulfonyl-2,3-O-isopropylidene-β-D-lyxopyranoside(16 g) in DMF (300 mL) was cooled to 0° C. Lithium azide (12.5 g, 255.6mmol) was added and stirred at 23° C. for 3 h. The reaction mixture wasdiluted with toluene (200 mL) and the volatiles were evaporated. Theresidue was dissolved in a mixture of CH₂ Cl₂ (500 mL) and water (200mL). The organic layer was separated and washed with water (2×250 mL),brine (300 mL), dried (NaSO₄) and evaporated to obtain an oily residuewhich upon purification by flash silica gel chromatography usinghexane/ethyl acetate (100/0; 97.5/2.5; and 95/5) as the eluent affordedpure azido product 116 (5.74 g, 50.2%). ¹ H NMR (300 MHz, (CDCl₃): δ1.38 (s, 3H, CH₃), 1.55 (s, 3H, CH₃), 3.44 (s, 3H, OCH₃), 3.7-3.9 (m,3H), 4.03 (dd, 1H, J=6.32 & 3.85 Hz), 4.49 (d, 1H, J=3.84 Hz), 4.52 (m,1H).

Example 92N-Acetyl-4-amino-4-deoxy-2,3-O-isopropylidene-β-L-methyl-ribopyranoside(117)

To a solution of 116 (12.1 g, 52.83 mmol) in MeOH (40.0 mL) was addedPd/C (5% w/w, 1.2 g) and the reaction mixture was shaken well under H₂(50 psi) atmosphere at room temperature for 1 h. The TLC (30% ethylacetate/hexane) indicated completion of the reaction. The reactionmixture was filtered over celite bed and the filtrate evaporated todryness, and co-evaporated with toluene (2×50 mL) and pyridine (2×25mL). This residue was then carried forward for the next reaction withoutfurther purification.

To the above crude mixture was added DMAP (0.7 g, 5.0 mmol), pyridine(25.0 mL, 310.55 mmol) in CH₂ Cl₂ (250.0 mL) followed by aceticanhydride (25.0 mL, 265.0 mmol) at -5° C. (ice-acetone bath). After theaddition, the cooling bath was removed and the reaction mixture wasstirred for 16 h. The TLC (100% ethyl acetate) indicated completion ofthe reaction. MeOH (10.0 mL) was added and the volatiles wereevaporated. The residue was dissolved in CH₂ Cl₂ (300 mL) and thissolution was then washed with water (2×200 mL) and brine (200 mL), dried(Na₂ SO₄) and evaporated. The residue was purified by flashchromatography using ethyl acetate/hexane (from 5/95 to 20/80 to 60/40to 80/20) as the eluent to obtain the product 117 (in a combined yieldof 11.49 g, 88.83%). ¹ H NMR (300 MHz, (CDCl₃): δ 1.34 (s, 3H, CH₃),1.51 (s, 3H, CH₃), 1.99 (s, 3H, COCH₃), 3.37 (t, 1H), 3.83 (dd, 1H,J=5.77 & 5.49 Hz), 4.01 (t, 1H, J=5.77 & 4.67 Hz), 4.35 (t, 1H, J=5.5 &4.67 Hz), 4.40 (d, 1H, J=4.4 Hz), 4.54 (m, 1H), 5.76 (bd, 1H, J=7.97Hz),.

Example 93 1,2,3,5-Tetra-O-acetyl-4-deoxy-4-(acetamido)-L-ribofuranose(118)

A solution of 117 (8.9 g) in a mixture of distilled water and AcOH (1:1,100 mL) was heated at 70-75° C. for 1.5 h. TLC (100% ethyl acetate)indicated completion of the reaction. Absolute EtOH (2×50 mL) was addedand co-evaporated to obtain a dry solid residue. To this solid was addeda mixture of glacial acetic acid and acetic anhydride (100.0 mL, 1:1)and cooled to 0° C. (ice-water bath), and treated with conc. H₂ SO₄ (1.0mL). The reaction mixture was stirred at 0° C. for 30 min and then keptat 4° C. for 2 days. The reaction mixture was treated with anhydrousNaOAc (10.0 g) and stirred at room temperature for 30 min. The reactionmixture was then poured into ice-water mixture (400 mL) and extractedwith CH₂ Cl₂ ((2×250 mL). The combined organic layer was washed withwater (2×500 mL) and brine (400 mL), dried (Na₂ SO₄) and evaporated. Thecrude product that obtained was purified by flash chromatography usingethyl acetate/hexane (25/75 to 50/50) as the eluent to obtain 118 (6.6g, 50.67%). ¹ H NMR (300 MHz, (CDCl₃): δ 2.0-2.12 (m, 15H, 5xCOCH₃),4.18-4.51 (m, 3H), 5.33-5.36 (m, 1H), 5.45-5.55 (m, 1H), 6.36 (s,0.75H), 6.55 (d, 0.25H, J=5.22 Hz).

Example 94Methyl-1-(2',3',5'-triacetyl-4'-deoxy-4'-acetamido-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate(119)

A suspension of methyl-1,2,4-triazole-3-carboxylate (1.022 g, 8.05 mmol)and ammonium sulphate (100 mg) in hexamethyldisilazane (20 mL) wasrefluxed for 2.5 h under N₂ atmosphere. The volatiles were evaporatedand the residue was suspended in 1,2-dichloroethane (50 mL). It was thentreated with a solution of 118 (2.513 g, 7 mmol) in 1,2-dichloroethane(50 mL). To the reaction mixture was then added fuming SnCl₄ (0.94 mL,8.05 mmol) at 0-5° C. (ice-water bath). The reaction mixture was stirredat room temperature for 1 h. The reaction was carefully quenched withsaturated solution of NaHCO₃ (50 mL) and diluted with CH₂ Cl₂ (200 mL).The mixture was filtered over a celite bed (5 g) and washed with CH₂ Cl₂(100 mL). The organic layer of the filtrate was separated and theaqueous layer was extracted with CH₂ Cl₂ (2×100 mL). The combinedorganic layer was washed with water (2×300 mL) and brine (500 mL), dried(Na₂ SO₄) and evaporated. The crude residue was recrystallized fromethyl acetate (40 mL) to obtain pure titled product 119 (1.8 g, 60.36%).¹ H NMR (300 MHz, (CDCl₃): δ 2.03-2.14 (m, 12H, 4xCOCl₁₃), 3.93 (s, 3H,OCH₃), 4.2 (m, 1H, H_(5')), 4.41 (m, 2H, H_(4') & H_(5')), 5.64 (d, 1H,H_(3'), J=4.67 Hz), 6.16 (t, 1H, H₂, J=4.95 & 5.77 Hz), 6.27 (d, 1H,H_(1'), J=6.05 Hz), 8.46 (s, 0.86H, major rotamer, C₅ H), 8.60 (s,0.14H, minor rotamer, C₅ H). Anal. Calcd. for C₁₇ H₂₂ N₄ O₉ : C, 47.89;H, 5.20; N. 13.14. Found: C, 47.77; H, 5.49; N, 13.04.

Example 951-(4'-Deoxy-4'-acetamido-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide(120)

A solution of 119 (3.26 g, 7.65 mmol) in saturated methanolic ammonia(100 mL) was stirred at room temperature for 16 h. The reaction wasevaporated to dryness and the residue was purified by flashchromatography over alumina using the solvent mixture ethylacetate/n-propyl alcohol/ water (lower layer, 64/4/32 to 57/14/29%) toafford the titled product 120 (1.7 g, 77.98%). ¹ H NMR (300 MHz,(DMSO-d₆ +D₂ O): δ 1.64 (s, 0.75H, COCH₃, minor rotamer (min)), 2.0 (s,2.25H, COCH₃ major rotamer (maj)), 3.84-3.54 (m, 3H, H_(-4') & H_(-5')),4.1 (m, 1H, H_(-3')), 4.32 (t, 0.25H, J=4.4 Hz, H₋₂ ',min), 4.56 (t,0.75H, J=4.2 Hz, H_(-2'), maj), 5.82 (d, 0.75H, J=6.32 Hz, H_(-1'),maj), 6.01 (d, 0.25H, J=4.4 Hz, H_(-1'), min), 8.74 (s, 0.75H, C₅ H,maj), 8.96 (s, 0.25H, C₅ H, min). ). Anal. Calcd. for C₁₀ H₁₅ N₅ O₅ : C,42.10; H, 5.30; N. 24.55. Found: C, 42.44; H, 5.49; N, 24.69.

Example 961-[(3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-L-ribofuranosyl]-1,2,4-triazole-3-carboxamide(121)

A suspension of 120 (0.75 g, 2.63 mmol) in pyridine (15 mL) was treatedwith 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (1.09 mL, 3.42 mmol)and stirred at room temperature for 16 h. The reaction mixture wascarefully quenched with saturated solution of NaHCO₃ (5 mL) and dilutedwith CH₂ Cl₂ (100 mL). The organic layer was separated and the aqueouslayer was extracted with CH₂ Cl₂ (2×25 mL). The combined organic layerwas washed with water (2×100 mL) and brine (100 mL), dried (Na₂ SO₄) andevaporated. The crude residue that obtaine was purified by flashchromatography over silica gel using CHCl₃ /MeOH (100/0-98/2-95/5-90/10)as the eluent to afford the product 121 (0.75 g, 54%). ¹ H NMR (300 MHz,CDCl₃): δ 0.93-1.17 (m, 24H), 1.37 (m, 2H), 2.01 (s, 1H, COCH₃, minorrotamer (min)), 2.14 (s, 2H, COCH₃, major rotamer (maj)), 2.98 (s,0.34H, OH, exchangeable, min), 3.34 (s, 0.66H, OH!, exchangeable, maj),3.78-3.84 (m, 1H, H_(5')), 3.97-4.14 (m, 2H, H_(4') & H_(5')), 4.33 (d,0.34H, J=4.12 Hz, H_(2'), min), 4.41 (d, 0.66H, J=4.95 Hz, H_(2'), maj),4.52 (m, H_(4'), min), 4.65 (m, H_(3'), min), 5.28 (t, J=4.95 Hz,H_(3'), maj), 5.80 (s, 0.66H, exchangeable, maj), 5.95 (s, 0.34H,exchangeable, min), 5.97 (s, 0.34H, H_(1'), min), 6.39 (s, 0.66H,H_(1'), maj), 6.89 (s, 0.66H, exchangeable, maj), 7.00 (s, 0.34H,exchangeable, min), 8.37 (s, 0.66H, C₅ H, maj), 8.52 (s, 0.34H, C₅ H,min).

Example 97 1-[2'-O-(p-Toluoylthionoformyl)-3',5'-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-L-ribofuranosyl]-1,2,4-triazole-3-carboxamide(122).

To a solution of 121 (0.65 g, 1.23 mmol) in a mixture of CH₂ Cl₂ (9 mL)and pyridine (1 mL) was added O-(p-tolyl)thionochloroformate (0.285 mL,1.85 mmol) and the reaction mixture was stirred at room temperature for16 h. The reaction mixture was quenched with saturated solution ofNaHCO₃ (5 mL) and diluted with CH₂ Cl₂ (100 mL). The organic layer wasseparated and the aqueous layer was extracted with CH₂ Cl₂ (2×25 mL).The combined organic layer was washed with water (2×100 mL) and brine(100 mL), dried (Na₂ SO₄) and evaporated. The crude residue thatobtained was purified by flash chromatography over silica gel usingCHCl₃ /ethyl acetate (100/0-95/5-90/10) as the eluent to afford theproduct 122 (0.33 g, 39.52%). ¹ H NMR (300 MHz, CDCl₃): δ 0.92-1.15 (m,24H), 1.29 (m, 2H), 2.01 (s, 1H, COCH₃, minor rotamer (min)), 2.19 (s,2H, COCH₃, major rotamer (maj)), 2.35 (s, 3H, CH₃), 3.92 (m, 1H,H_(5')), 4.07 (m, 2H, H_(4') & H_(5')), 4.68-4.8 (m, H_(3'), min), 5.50(m, H_(3'), maj), 5.7 (s, 0.66H, exchangeable, maj), 5.82 (s, 0.34H,exchangeable, min), 6.10 (d, 1H, J=4.94 Hz, H₂.), 6.17 (s, 0.34H,H_(1'), min), 6.54 (s, 0.66H, H_(1'), maj), 6.70 (s, 0.34H,exchangeable, min), 6.86 (s, 0.66H, exchangeable, maj), 6.96 (d, 2H,J=8.52 Hz, aromatic-H), 7.21 (d, 2H, J=8.24 Hz aromatic-H), 8.40 (s,0.66H, C₅ H, maj), 8.69 (s, 0.34H, C₅ H, min).

Example 98 1-[(3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-2',4'-dideoxy-4'-acetamido-β-L-ribofuranosyl]-1,2,4-triazole-3-carboxamide(123)

A solution of 122 (0.325 g, 0.48 mmol) in toluene (20 mL) was purgedwith argon for 20 min. To the solution were added2,2'-azobisisobutyronitrile (0.078 g, 0.48 mmol) and tributyltin hydride(0.25 mL, 0.96 mmol). The reaction mixture was refluxed for 6 h under astream of argon. The reaction was evaporated to dryness and the cruderesidue was purified by flash chromatography over silica gel using CHCl₃/ethyl acetate (100/0-90/10-70/30-40/60-20/80-0/100) as the eluent toafford 123 (0.22 g, 89.68%). H NMR (300 MHz, CDCl₃): δ 0.92-1.15 (m,24H), 1.28 (m, 2H), 2.0 (s, 0.66H, COCH₃, minor rotamer (min)), 2.13 (s,2.34H, COCH₃, major rotamer (maj)), 2.36-2.58 (m, 1H, 112.), 2.85 (dd,1H, J=13.73 & 7.41 Hz, H_(2')), 3.74-4.09 (m, 3H, H_(4') & H_(5')),4.49-4.67 (m, H_(3'), min), 5.30 (m, H_(3'), maj), 5.83 (s, 0.8H,exchangeable, maj), 5.94 (s, 0.2H, exchangeable, min), 6.14 (d, 0.2H,J=6.05 Hz, H_(1') min), 6.54 (d, 0.8H, J=8.24 Hz, H_(1'), maj), 6.89 (s,0.8H, exchangeable, maj), 7.04 (s, 0.2H, exchangeable, min), 8.35 (s,0.8H, C₅ H, maj), 8.55 (s, 0.2H, C₅ H, min).

Example 991-(2',4'-Dideoxy-4'-acetamido-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide(124)

A solution of 123 (0.2 g, 0.39 mmol) in CH₂ Cl₂ (5 mL) was treated withtriethylamine tris-hydrofluoride (0.25 mL, 1.56 mmol) at roomtemperature. The reaction mixture was stirred for 48 h and the volatileswere evaporated to dryness. The residue was purified by flashchromatography over silica gel using CHCl₃ /MeOH(100/0-95/5-90/10-85/15) as the eluent to afford 124 (0.08 g, 66%). ¹ HNMR (300 MHz, CD₃ OD): δ 1.95 (s, 0.36H, COCH₃, minor rotamer (min)),2.16 (s, 2.64H, COCH₃, major rotamer (maj), 2.51 (m, 1H, H_(2')), 2.87(m H, H₂), 3.82 (m, 2H,H_(5')),3.99(t, 1H,J=6.87 Hz, H₄),4.44 (d,1H,J=4.12 Hz, H₃), 6.54 (t, 1H,J=7.69 Hz, H_(1')), 8.63 (s, 0.88H, C₅ H,maj), 8.88 (s, 0.12H, C₅ H, min). Anal. Calcd. for C₁₀ H₁₅ N₅ O₄ : C,44.60; H, 5.62; N, 26.01. Found: C, 44.69; H, 5.71; N, 26.10.

Example 1001-(2',3',5'-Tri-O-acetyl-4'-deoxy-4'-acetamido-β-L-ribofuranosyl)thymine(125)

A suspension of thymine (1.26 g, 10 mmol) and ammonium sulphate (126 mg)in hexamethyldisilazanc (25 mL) was refluxed for 5 h under N₂atmosphere. The reaction mixture was evaporated to dryness and theresidue suspended in 1,2-dichloroethane (50 mL). A solution of 118(2.513 g, 7 mmol) in 1,2-dichloroethane (50 mL) was added followed byfuming SnCl₄ (1.17 mL, 10 mmol, 1.42 eq) at 0-5° C. (ice-water bath).The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was carefully quenched with saturated solution ofNaHCO₃ (50 mL) and diluted with CH₂ Cl₂ (200 mL). The mixture wasfiltered over a celite bed (5 g) and washed with CH₂ Cl₂ (100 mL). Theorganic layer of the filtrate was separated and the aqueous layer wasextracted with CH₂ Cl₂ (2×100 mL). The combined organic layer was washedwith water (2×300 mL) and brine (500 mL), dried (Na₂ SO₄) andevaporated. The residue obtained was purified by flash chromatographyover silica gel using CHCl₃ /acetone (95/5-90/10-85/15-80/20) as theeluent to obtain pure titled product 125 (2.9 g, quantitative). ¹ H NMR(300 MHz, CDCl₃): δ 1.89-2.2 (m, 15H, 4XCOCH₃ & C₅ CH₃), 4.08 (m, 0.5H,H_(5')), 4.37-4.56 (m, 2.5H, H_(4') & H_(5')), 5.32 (m, 0.5H, H_(3')),5.47 (m, 1.5H, H₂ & H₃), 6.15 (m, 0.5H, H_(1')), 6.37 (d, 0.5H, J=6.6Hz, H_(1')), 7.16 (s, 0.5H, C.sub. H), 7.44 (s, 0.5H, C₆ H), 9.02 (s,0.5H, NH, exchangeable), 9.20 (s, 0.5H, NH, exchangeable).

Example 101 1-(4'-Deoxy-4'-acetamido-β-L-ribofuranosyl)thymine (126)

A solution of 125 (3.1 g, 7.29 mmol) in saturated methanolic ammonia(100 mL) was stirred at room temperature in a steel bomb for 16 h. Thesteel bomb was cooled to 0° C., opened and evaporated to dryness. Theresidue was purified by flash silica gel chromatography over silica gelusing CHCl₃ /MeOH (95/5-90/10-85/15) as the eluent to afford the titledproduct 126 (1.72, 78.86%). ¹ H NMR (300 MHz, (DMSO-d₆ +D₂ O): δ 1.70(s, 1.35H, COCH₃, minor rotamer (min)), 1.73 (s, 1.35H, C₅ CH₃), 1.77(s, 1.65H, C₅ CH₃), 1.98 (s, 1.65H, COCH₃, major rotamer (maj),3.95-3.57 (m, 4H, H₃, H_(4') & H_(5')), 4.13 (t, 0.55H, J=4.67 Hz,H_(2'), maj), 4.20 (dd, 0.45H, J=4.4 Hz, H_(2'), min), 5.72 (d, 0.45H,J=6.6 Hz, H_(1'), min), 5.88 (d, 0.55H, J=5.77 Hz, H_(1'), maj), 7.68(s, 0.45H, C₆ H, min), 8.00 (s, 0.55H, C₆ H, maj). Anal. Calcd. for C₁₂H₁₇ N₃ O₆ : C, 48.16; H, 5.73; N, 14.04. Found: C, 48.23; H, 5.81; N,14.29.

Example 1021-[(3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-L-ribofuranosyl]thymine(127) &1-[(2',3'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-4'-dideoxy-4'-acetamido-β-L-ribofuranosyl]thymine(128)

A suspension of 126 (1.72 g, 5.75 mmol) in pyridine (25 mL) was treatedwith 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (2.75 mL, 8.59 mmol)and stirred at room temperature for 16 h. The reaction mixture wascarefully quenched with saturated solution of NaHCO₃ (5 mL) and dilutedwith CH₂ Cl₂ (100 mL). The organic layer was separated and the aqueouslayer was extracted with CH₂ Cl₂ (2×25 mL). The combined organic layerwas washed with water (2×100 mL) and brine (100 mL), dried (Na₂ SO₄) andevaporated. The crude residue was purified by flash chromatography oversilica gel using hexane/ethyl acetate (90/10-80/20-60/40-20/80-0/100) asthe eluent to afford a mixture of inseparable regio isomeric products127 & 128 (2.15 g, 69%). ¹ H NMR (300 MHz, CDCl₃): δ 1.0 (m), 1.9-2.13(m), 3.79-4.13 (m), 4.3-4.47 (m), 4.74 (d), 5.07-5.21 (m), 5.47 (s),5.84 (s), 5.93 (d, J=3.3 Hz), 7.20 (s), 7.40 (s), 7.53 (s), 7.78 (s),8.88 (s), 9.13 (s), 9.67 (s).

Example 1031-[2'-O-(p-Tolylthionoformyl)-3',5'-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-L-ribofuranosyl]thymine(129) &1-[5'-O-(p-Tolylthionoformyl)-2',3'-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-4'-deoxy-4'-acetamido-β-L-ribofuranosyl]thymine(130)

To a mixture of 127 and 128 (2 g, 3.69 mmol) in pyridine (20 mL) wasadded O-(-toluoyl)thionochloroformate (0.712 mL, 4.43 mmol) and thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with saturated solution of NaHCO₃ (5 mL) anddiluted with CH₂ Cl₂ (100 mL). The organic layer was separated and theaqueous layer was extracted with CH₂ Cl₂ (2×25 mL). The combined organiclayer was washed with water (2×100 mL) and brine (100 mL), dried (Na₂SO₄) and evaporated. The crude residue was purified by flashchromatography over silica gel hexane/ethyl acetate(90/10-80/20-70/30-40/60) as the eluent to afford a faster product (0.9g) and a slower product (0.8 g). The combined yield of both the productswas 1.7 g (66.54%). The H NMR analysis of both the products indicatedthat the slower product was 129 while the faster product was 130. 129: ¹H NMR (300 MHz, CDCl₃): δ 0.98-1.06 (m, 24H), 1.89 (s, 3H, CH₃), 2.00(s, 2H, COCH₃, major rotamer,(maj)), 2.25 (s, 1H, COCH₃, minorrotamer,(min)), 2.34 (s, 3H, CH₃), 3.85-4.03 (m, 2H, H_(5')), 4.38-4.80(m, 2H, H_(3') & H_(4')), 5.3 (m, 0.24H, H_(2'), min), 5.7 (m, 0.76H,H_(2'), maj), 6.01 (s, 1H, H_(1')), 6.95 (d, 2H, J=8.52 Hz, aromatic-H),7.20 (d, 2H, J=8.52 Hz, aromatic-H), 7.35 (s, 0.24H, C₆ H), 7.57 (s,0.76H, C₆ H), 8.23 (bs, 0.24H, NH, exchangeable), 8.64 (s, 0.76H, NH,exchangeable). 130: ¹ H NMR (300 MHz, CDCl₃): δ 1.00-1.06 (m, 26H), 1.87(s, 3H, CH₃), 2.02 (s, 2.4H, COCH₃, major rotamer,(maj)), 2.22 (s, 0.6H,COCH₃ , minor rotamer,(min)), 4.22-4.5 (m, 3H, H_(4') & H_(5')), 4.88(m, 1H, H_(3')), 5.22 (m, 1H, H_(2')), 6.01 (d, 1H, J=3.02 Hz, H,), 6.94(d, 2H, J=8.24 Hz, aromatic-H), 7.21 (d, 2H, J-=8.52 Hz, aromatic-H),7.78 (s, 1H, C₆ H), 8.38 (bs, 0.16H, NH, exchangeable, min), 8.44 (s,0.84H, NH, exchangeable, maj).

Example 1041-[(3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-2',4'-dideoxy-4'-acetamido-β-L-ribofuranosyl]thymine(131)

A solution of 129 (0.74 g, 1.070 mmol) in toluene (25 mL) was purgedwith argon for 20 min. To this solution was added2,2'-azobisisobutyronitrile (0.174 g, 1.074 mmol) followed bytributyltinhydride (0.56 mL, 2.113 mmol, 2 eq). The reaction mixture wasrefluxed for 6 h under a stream of argon. The volatiles were evaporatedand the crude residue was purified by flash chromatography over silicagel using hexane/ethyl acetate (100/0-90/10-80/20-70/30-60/40) as theeluent to afford 131 (0.45 g, 80.03%). ¹ H NMR (300 MHz, CDCl₃): δ0.98-1.06 (m, 24H), 1.26 (m, 2H), 1.90 (s, 3H, CH₃), 1.97 (s, 2.25H,COCH₃, major rotamer,(maj)), 2.17 (s, 0.75 H, COCH₃, minorrotamer,(min)), 2.2-2.4 (H , 1.5H, H_(2')), 2.65 (m, 0.5H, H_(2')), 3.67(mn, 1H, H_(5')), 4.0 (m, 1H, H_(5')), 4.32 (m), 4.64 (m, 1H, H_(4')),5.12 (m, 1H, H_(3')), 5.71 (m, 0.15H, H_(1'), min), 6.05 ((, 0.85H,J=6.05 Hz, H_(1'), maj), 7.33 (s, 0.15H, C₆ H, min), 7.53 (s, 0.85H, C₆H, maj), 8.23 (bs, 0.45H, NH, exchangeable, min), 8.76 (s, 0.85H, NH,exchangeable, maj).

Example 105 1-(2',4'-Dideoxy-4'-acctamido-β-L-ribofuranosyl)thymine(132)

A solution of 131 (0.38 g, 0.72 mmol) in CH₂ Cl₂ (10 mL) was treatedwith tiethylamine tris-hydrofluoride (0.585 mL, 3.6 mmol) at roomtemperature. The reaction mixture was stirred for 48 h and evaporated todryness. The residue was purified by flash chromatography over silicagel using CHCl₃ /MeOH (100/0-97/3-94/6-90/10) as the eluent to thetitled compound 132 (0.19 g, 92.75%). ¹ H NMR (300 MHz, CD₃ OD): δ 1.83(s, 1.35H, C₅ CH₃), 1.86 (s, 1.65H, C₅ CH₃), 1.95 (s, 1.35H, COCH₃,minor rotamer (min), 2.18 (s, 1.65H, COCH₃, major rotamer (maj)), 2.37(m, 2H, H_(2')), 4.05-3.73 (min, 3H, H_(4') & H_(5')), 4.32 (d, 0.55H,J=3.85 Hz, H_(3'), maj), 4.36 (bs, 0.45H, H_(3'), min), 6.26 (t, 0.45H,J=8.2 Hz, H_(1'), m), 6.49 (t, 0.55H , J=7.4 Hz, H_(1'), maj), 7.70 (s,0.55H, C₆ H, maj), 8.18 (s, 0.45H, C₆ H, min). Anal. Calcd. for C₁₂ H₁₇N₃ O₅.1/2H₂ O: C, 49.31; H, 6.21; N, 14.38. Found: C, 49.49; H, 6.43; N,14.51.

Example 106 1-[(2',3'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-5',4'-dideoxy-4'-acetamido-β-L-ribofuranosyl]thymine (133)

A solution of 130 (1.35 g, 1.954 mmol) in toluene (40 mL) was purgedwith argon for 20 min. To this solution was added 2,2'-azobisisobutyronitrile (0.32 g, 1.954 mmol) and tributyltinhydride(1.035 mL, 3.905 mmol). The reaction mixture was refluxed for 1.5 hunder a stream of argon. The reaction mixture was evaporated to dryness.The crude residue was purified by flash chromatography over silica gelusing hexane/ethyl acetate (100/0-90/10-80/2 0-70/ 30-60/40) as theeluent to a 13 (0.7 g, 68.24%). ¹ H NMR (300 MHz, CDCl₃): δ 0.98-1.05(m, 24H), 1.24 (m, 2H), 1.46 (d, 1.2H, H_(5'), minor rotamer(min), 1.52(d, 2.8H, J=6.9 Hz, H_(5'), major rotamer(maj), 1.89 (s, 1.2H, COCH₃,min), 1.93 (s, 3H, CH₃), 2.09 (s, 2.8H, COCH₃, maj), 3.86 (m, 0.6H,H_(4'), maj), 3.98 (m, 0.4H, H_(4'), m), 4.12-4.36 (m, 1H, H_(3')), 5.18(m, 1H, H_(2')), 5.30 (d, 0.6H, J=6.05 Hz, J=6.05 Hz, H_(1'), maj), 5.98(d, 0.4H, J=3.57 Hz, H_(1'), min), 6.99 (s, 0.4H, C₆ H, min), 7.08 (s,0.6H, C₆ H, maj), 8.53 (bs, 0.6H, NH, exchangeable, maj), 8.66 (bs,0.4H, NH, exchangeable, min).

Example 107 1(5','4'-Dideoxy-4'-acetamido-β-L-ribofuranosyl)thymine(134)

A solution of 133 (0.6 g, 1.14 mmol) in CH₂ Cl₂ (20 mL) was treated withtriethylamine tris-hydrofluoride (0.558 mL, 3.42 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 20h and the volatiles were evaporated to dryness. The residue was purifiedby flash chromatography over silica gel using CHCl₃ /MeOH(100/0-97/3-94/6-90/10) as the eluent to afford 134 (0.2 g, 61.83%). ¹ HNMR (300 MHz, (CD₃ OD): δ 1.40 (d, 0.36H, J=6.87 Hz, H_(5'), minorrotamer (min)), 1.48 (d, 0.64H, J=6.87 Hz, H_(5'), major rotamer (maj)),1.87 (s, 1.08H , C₅ CH₃), 1.91 (s, 1.92H, C₅ CH₃),1.91 (s, 1.08H ,COCH₃, min), 2.09 (s, 1.92H , COCH₃, maj), 3.84-4.09 (m, 2H, H_(3') &H_(4')), 4.33 (m, 0.36H, H_(2'), min), 4.67 (m, 0.64H , H_(2'), maj),5.71 (d, 0.64H, J=6.87 Hz, H_(1'), maj), 6.08 (d, 0.36H, J=5.77 Hz,H_(1'), min ), 7.21 (s, 0.36H , C₆ H, min), 7.27 (s, 0.64H , C₆ H, maj).Anal. Calcd. for C₁₂ H₁₇ N₃ O₅ : C, 50.88; H, 6.05; N, 14.83. Found: C,50.91; H, 6.23; N, 14.91.

Example 1081-(2',3',5'-O-Triacetyl-4'-deoxy-4'-acetamido-β-L-ribofuranosyl)-6-azauracil(135)

A suspension of 6-azauracil (0.909 g, 8.05 mmol) and ammonium sulphate(100 mg) in hexamethyldisilazane (20 mL) was refluxed for 2 h under N₂atmosphere. The reaction mixture was evaporated to dryness and theresidue was suspended in 1,2-dichloroethane (50 mL). To this stirredsolution was added a solution of 118 (2.513 g, 7 mmol) in1,2-dichloroethane (50 mL) followed by fuming SnCl₄ (0.94 mL, 8.05 mmol,1.15 eq) at 0-5° C. (ice-water bath). The reaction mixture was stirredat room temperature for 16 h. The reaction mixture was carefullyquenched with saturated solution of NaHCO₃ (50 mL) and diluted with CH₂Cl₂ (200 mL). The mixture was filtered over a celite bed (5 g) andwashed with CH₂ Cl₂ (100 mL). The organic layer of the filtrate wasseparated and the aqueous layer was extracted with CH₂ Cl₂ (2×100 mL).The combined organic layer was washed with water (2×300 mL) and brine(500 mL), dried (Na₂ SO₄) and evaporated. The crude residue was purifiedby flash chromatography over silica gel using hexane/ethylacetate(85/15-70/30-50/50-30/70-0/100) as the eluent to obtain the titledproduct 135 (0.5 g, 17%). ¹ H NMR (300 MHz, CDCl₃): 2.01-2.15 (m, 12H),4.12-4.48 (m, 3H, H_(4') & H_(5')), 5.47 (m, 1H, H_(3')), 5.57 (m, 0.2H,H_(2'), minor rotamer (min)), 5.64 (m, 0.8H, H_(2'), major rotamer(maj)), 6.41 (d, 0.2H, J=5.4 Hz, H_(1'), min), 6.52 (d, 0.8H, J7.2 Hz,H_(1'), maj), 7.38 (d, 0.6H, J=2.1 Hz, C₅ H, maj), 7.54 (s, 0.4H, C₅ H,min), 9.22 (bs, 0.6H, NH, exchangeable, maj), 9.46 (bs, 0.4H, NH,exchangeable, min).

Example 1091-(2',3',5'-O-Triacetyl-4'-deoxy-4'-acetamido-β-L-ribofuranosyl)-6-carbomethoxy-uracil(136)

A suspension of 6-carbomethoxyuracil (1.7 g, 10 mmol) and ammoniumsulphate (170 mg) in hexamethyldisilazane (25 mL) was refluxed for 2 hunder N₂ atmosphere. The volatiles were evaporated and the residue wassuspended in 1,2-dichloroethane (50 mL). To this was added a solution of118 (2.513 g, 7 mmol) in 1,2-dichloroethane (50 mL) followed by fumingSnCl₄ (1.17 mL, 10 mmol, 1.42 eq) at 0-5° C. (ice-water bath). Thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was carefully quenched with saturated solution of NaHCO₃ (50 mL)and diluted with CH₂ Cl₂ (200 mL). The mixture was filtered over acelite bed (5 g). The organic layer of the filtrate was separated andthe aqueous layer was extracted with CH₂ Cl₂ (2×100 mL). The combinedorganic layer was washed with water (2×300 mL) and brine (500 mL), dried(Na₂ SO₄) and evaporated. The crude residue was purified by flashchromatography over silica gel using hexane/ethylacetate(95/5-80/20-70/30-50/50) as the eluent to obtain pure titled product 136(2.2 g, 67%). ¹ H NMR (300 MHz, CDCl₃): 1.99-2.10 (m, 12H), 3.92 (s, 2H,OCH₃, major rotamer (maj)), 3.98 (s, 1H, OCH₃, minor rotamer (min)),4.00-4.07 (m, 1H, H_(5')), 4.53 (m, 2H, H_(4') & H_(5')), 5.48 (d, 0.8H,J=4.67 Hz, H_(3'), maj), 5.53 (d, 0.2H, J=4.94 Hz, H_(3'), min), 6.13(m, 0.2H, H_(2'), min), 6.20 (dd, 0.8H, J=4.67 & 7.96 Hz, H_(2'), maj),6.30 (s, 0.8H, H_(1'), maj), 6.37 (s, 0.2H, H_(1'), min), 6.58 (d, 0.2H,J=6.87 Hz, C₅ H, min), 6.68 (d, 0.8H, J=7.99 Hz, C₅ H, maj), 8.70 (bs,0.8H, NH, exchangeable, maj), 8.89 (bs, 0.2H, NH, exchangeable, min).

Example 1101-(2',3',5'-O-Triacetyl-4'-deoxy-4'-acetamido-β-L-ribofuranosyl)-5-fluorouracil(137)

A suspension of 5-fluorouracil (1.3 g, 10 mmol) and ammonium sulphate(130 mg) in hexamethyldisilazane (25 mL) was refluxed for 4 h under N₂atmosphere. The reaction mixture was evaporated to dryness and theresidue was suspended in 1,2-dichloroethane (50 mL). The solution wasthen treated with a solution of 118 (2.513 g, 7 mmol) in1,2-dichloroethane (50 mL) followed by fuming SnCl₄ (1.17 mL, 10 mmol,1.42 eq) at 0-5° C. (ice-water bath). The reaction mixture was stirredat room temperature for 16 h. The reaction mixture was carefullyquenched with saturated solution of NaHCO₃ (50 mL) and diluted with CH₂Cl₂ (200 mL). The mixture was filtered over a celite bed (5 g). Theorganic layer of the filtrate was separated and the aqueous layer wasextracted with CH₂ Cl₂ (2×100 mL). The combined organic layer was washedwith water (2×300 mL) and brine (500 mL), dried (Na₂ SO₄) andevaporated. The crude residue was purified by flash chromatography oversilica gel using CHCl₃ /acetone (80/20) as the eluent to provide pureproduct 137 (1 g, 33.30%). ¹ H NMR (300 MHz, CDCl₃): 2.02-2.21 (m, 12H),4.10 (m, 0.5H, H_(5')), 4.43-4.56 (m, 2.5H, H_(4') & H_(5')), 5.30 (m,0.5H, H_(3')), 5.43-5.54 (m, 1.5H, H_(2') & H_(3')), 6.09 (t, 0.5H,J=6.32 & 4.94 Hz, H_(1')), 6.28 (d, 0.5H, J=4.94 Hz, H_(1')), 7.48 (d,0.5H, J=5.77 Hz, C₆ H), 7.95 (d, 0.5H, J=5.77 Hz, C₆ H), 9.19 (bs, 0.5H,NH, exchangeable), 9.34 (bs, 0.5H, NH, exchangeable).

Example 1111-(2',3',5'-O-Triacetyl-4'-deoxy-4'-acetamido-β-L-ribofuranosyl)-5-fluorocytosine(138)

A suspension of 5-fluorocytosine (1.29 g, 10 mmol, 1.42 eq) and ammoniumsulphate (322 mg) in hexamethyldisilazane (40 mL) was refluxed for 4 hunder N₂ atmosphere. The volatiles were evaporated and the residue wassuspended in 1,2-dichloroethane (50 mL). To this stirred solution wasadded a solution of 118 (2.513 g, 7 mmol) in 1,2-dichloroethane (50 mL)followed by fuming SnCl₄ (1.17 mL, 10 mmol, 1.42 eq) at 0-5° C.(ice-water bath). The reaction mixture was stirred at room temperaturefor 16 h. The reaction mixture was carefully quenched with saturatedsolution of NaHCO₃ (50 mL) and diluted with CH₂ Cl₂ (200 mL). Themixture was filtered over a celite bed (5 g). The organic layer of thefiltrate was separated and the aqueous layer was extracted with CH₂ Cl₂(2×100 mL). The combined organic layer was washed with water (2×300 mL)and brine (500 mL), dried (Na₂ SO₄) and evaporated. The crude residuewas purified by flash chromatography over silica gel using CHCl₃/acetone (80/20) to obtain pure product 138 (1 g, 33.55%). ¹ H NMR (300MHz, CDCl₃): 1.98-2.18 (m, 12H), 4.08 (m, 0.5H, H_(5')), 4.37-4.61 (m,2.5H, H_(4') & H_(5')), 5.28 (m, 1H, H₃,), 5.44 (t, 0.8H, J=4.67 Hz,H_(2'), major rotamer (maj)), 5.55 (d, 0.2H, J=4.39 Hz, H_(2'), minorrotamer (min)), 5.76 (bs, 1H, NH₂, exchangeable), 6.27 (bt, 0.23H,H_(1'), min), 6.37 (d, 0.77H, J=3.57 Hz, H_(1'), maj), 7.49 (d, 0.23H,J=5.77 Hz, C₆ H, min), 7.79 (bs, 1H, NH₂, exchangeable), 7.94 (d, 0.77H,J=6.32 Hz, C₆ H, maj).

Example 112 1-(4'-Deoxy-4'-acetamido-β-L-ribofuranosyl)-6-azauracil(139)

A solution of 135 (0.45 g, 1.09 mmol) in saturated methanolic ammonia(10 mL) was stirred in a steel bomb at room temperature for 16 h. Thesteel bomb was cooled, opened and evaporated to dryness. The residue waspurified by flash chromatography over silica gel using CHCl₃ /MeOH(95/5-90/10-85/15) as the eluent to afford the titld product 139 (0.18g, 57.62%). ¹ H NMR (300 MHz, DMSO-d₆): δ 1.84 (s, 1.35H, COCH₃, minorrotamer (min)), 1.95 (s, 1.65H, COCH₃, major rotamer (maj)), 3.46-3.85(m, 3H, H_(4') & H_(5')), 4.01 (m, 1H, H_(-3')), 4.22 (m, 1H, H_(2')),4.89 (m, 0.45H, OH, min, exchangeable), 5.01 (m, 0.55H, OH, maj,exchangeable), ), 5.15 (s, 0.45H, OH, min, exchangeable), 5.28 (s,0.55H, OH, maj, exchangeable), 5.39 (d, 0.45H, J=6.86 Hz, OH, min,exchangeable), 5.50 (d, 0.55H, J=5.7 Hz, OH, maj, exchangeable), 6.0 (d,0.45H, J=7.15 Hz, H_(1'), min), 6.05 (d, 0.55H, J=5.5 Hz, H_(1'), maj),7.50 (s, 0.45H, C₅ H, min), 7.61 (s, 0.55H, C₅ H, maj), 12.2 (bs, 1H,NH, exchangeable). Anal. Calcd. for C₁₀ H₁₄ N₄ O₆ : C, 41.96; H, 4.93;N, 19.57. Found: C, 42.03; H, 5.11; N, 19.64.

Example 1131-(4'-Deoxy-4'-acetamido-β-L-ribofuranosyl)uracil-6-carboxamide (140)

A solution of 136 (2 g, 4.26 mmol) in saturated methanolic ammonia (20mL) was stirred at room temperature in a steel bomb for 16 h. The steelbomb was cooled, opened and evaporated to dryness. The residue thatobtained was purified by flash chromatography over silica gel usingCHCl₃ /MeOH (95/5-90/10-85/15) as the eluent to afford the titledproduct 140 (1 g, 71.49%). ¹ H NMR (300 MHz, DMSO-d₆ +D₂ O): δ 1.70 (s,1H, COCH₃, minor rotamer (min)), 1.89 (s, 2H, COCH₃, major rotamer(maj)), 3.97-3.44 (m, 4H, H_(3'), H_(4') & H_(5')), 4.73(m, 1H, H₂,),6.26-6.08 (m, 2H, C₅ H& H_(1')), Anal. Calcd. for C₁₂ H₁₆ N₄ O₇ : C,43.90; H, 4.91; N, 17.07. Found: C, 43.99; H, 5.06; N, 17.21.

Example 114 1-(4'-Deoxy-4'-acetamido-β-L-ribofuranosyl)-5-fluorouracil(141)

A solution of 137 (1 g, 2.33 mmol) in saturated methanolic ammonia (20mL) was stirred in a steel bomb at room temperature for 16 h. The steelbomb was cooled to 0° C., opened and evaporated to dryness. The residuewas purified by flash chromatography over silica gel using CHCl₃ /MeOH(95/5-90/10-85/15) as the eluent to afford the titled product 141 (0.6g, 84.95%). ¹ H NMR (300 MHz, (DMSO-d₆ +D₂ O): δ 1.72 (s, 1.35H, COCH₃,minor rotamer (min)), 1.83 (s, 1.65H, COCH₃, major rotamer (maj)),3.35-4.18 (m, 5H, H_(2'), H_(3'), H_(4') & H_(5')), 5.74 (d, 0.45H,J=5.77 Hz, H_(1'), min), 5.84 (d, 0.55H, J=4.1 Hz, H_(1'), maj), 8.25(s, 0.45H, C₆ H, min), 8.53 (s, 0.55H, C₆ H, maj), 11.77 (bs, 1H, NH,exchangeable). Anal. Calcd. for C₁₁ H₁₄ FN₃ O₆ : C, 43.57; H, 4.65; N,13.86. Found: C, 43.40; H, 4.71; N, 13.80.

Example 115 1-(4'-Deoxy-4'-acetamido-β-L-ribofuranosyl)-5-fluorocytosine(142)

A solution of 138 (1 g, 2.33 mmol) in saturated methanolic ammonia (20mL) was stirred in a steel bomb at room temperature for 16 h. The steelbomb was cooled to, opened and evaporated to dryness. The residue waspurified by flash chromatography over silica gel using CHCl₃ /MeOH(95/5-90/10-85/15) as the eluent to afford the titled product 142 (0.64g, 90.70%). ¹ H NMR (300 MHz, CD₃ OD): δ 1.92 (s, 2H, COCH₃, majorrotamer (maj)), 2.17(s, 1H, COCH₃, minor rotamer (min)), 3.75-3.93 (m,2H, H_(5')), 4.16-4.28 (m, 1.5H, H_(3') & H_(4')), 4.49 (t, 0.5H, J=4.4& 4.94 Hz, H_(3')), 4.65 (s, 1H, H_(2')), 5.77 (d, 0.33H, J=5.22 Hz,H_(1'), min), 6.11 (dd, 0.66H, J=1.92 & 4.12 Hz, H_(1'), maj), 8.19 (d,0.33H, J=6.86 Hz, C₆ H, min), 8.66 (d, 0.66H, J=7.15 Hz, C₆ H, maj).Anal. Calcd. for C₁₁ H₁₅ FN₄ O₅ : C, 43.71; H, 5.00; N, 18.54. Found: C,43.77; H, 5.17; N, 18.79.

It is to be understood that the above-described embodiments areillustrative only and that modifications thereof may occur to thoseskilled in the art. Accordingly, this invention is not to be regarded aslimited to the embodiments disclosed herein, but is to be limited onlyas defined by the appended claims.

We claim:
 1. The compound consisting essentially of L-ribavirin. OH. 2.A compound of claim 1 wherein the compound consisting essentially of anα-nucleoside.
 3. A compound of claim 2 wherein the compound consistingessentially of β-nucleoside.
 4. A pharmaceutical comprising a compoundaccording to claim 1, or a pharmaceutically acceptable ester or saltthereof, admixed with at least one pharmaceutically acceptable carrier.